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{\*\bkmkstart filing_1}{\*\bkmkend filing_1}{\*\bkmkstart doc_1_1}{\*\bkmkend doc_1_1}\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs2\ql \~\par\pard\plain\brdrb\brdrs\sa22\cf1\f51\fs2\ql \~\par\pard\plain\cf1\f51\fs2\ql \~\par\pard\plain\sb44\cf1\f51\fs32\b\qc UNITED STATES\par\pard\plain\cf1\f51\fs32\b\qc SECURITIES AND EXCHANGE COMMISSION\par\pard\plain\cf1\f51\fs20\b\qc Washington, D.C. 20549\par\pard\plain\brdrb\brdrs\li880\ri880\sa22\cf1\f51\fs2\qc \~\par\pard\plain\li880\ri880\sb44\cf1\f51\fs32\b\qc FORM 10-K\par\pard\plain\brdrb\brdrs\li880\ri880\sa22\cf1\f51\fs4\qc \~\par\pard\plain\sb44\cf1\f51\fs17\b\ql (Mark\~One)
\par\pard\plain
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\pard\plain\intbl\cf1\f51\fs22\ql \u9746?\cell\pard\plain\intbl\cf1\f51\fs22\b\ql ANNUAL REPORT PURSUANT TO SECTION\~13 OR 15(d) OF THE SECURITIES EXCHANGE\plain\intbl\cf1\f51\fs22\b\ql ACT OF\~1934\cell{
{\trowd\cellx748\cellx10800\trrh544\row}}}\pard\plain\sb44\cf1\f51\fs17\b\qc For the fiscal year ended December\~31, 2017\par\pard\plain\sb44\cf1\f51\fs17\b\qc OR
\par\pard\plain
{\trowd\cellx748\cellx10800\trrh589
\pard\plain\intbl\sb44\cf1\f51\fs22\ql \u9744?\cell\pard\plain\intbl\sb44\cf1\f51\fs22\b\ql TRANSITION REPORT PURSUANT TO SECTION\~13 OR 15(d) OF THE SECURITIES\plain\intbl\cf1\f51\fs22\b\ql EXCHANGE ACT OF\~1934\cell{
{\trowd\cellx748\cellx10800\trrh589\row}}}\pard\plain\sb44\cf1\f51\fs17\b\qc FOR THE TRANSITION PERIOD FROM\~\~\~\~\~\~\~\~\~\~\~\~\~\~TO\~\~\~\~\~\~\~\~\~\~\~\~\~\~\par\pard\plain\sb44\cf1\f51\fs17\b\qc Commission File Number\~001-37923\par\pard\plain\brdrb\brdrs\li880\ri880\sa22\cf1\f51\fs4\qc \~\par\pard\plain\sb44\cf1\f51\fs44\b\qc CRISPR THERAPEUTICS AG\par\pard\plain\cf1\f51\fs17\b\qc (Exact name of Registrant as specified in its Charter)\par\pard\plain\brdrb\brdrs\li880\ri880\sa22\cf1\f51\fs4\qc \~\par\pard\plain\cf1\f51\fs6\ql \~
\par\pard\plain
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\pard\plain\intbl\cf1\f51\fs17\b\qc Switzerland\cell\pard\plain\intbl\cf1\f51\fs17\b\qc Not Applicable\cell{
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\pard\plain\intbl\cf1\f51\fs15\b\qc (State or other jurisdiction of\par\pard\plain\intbl\cf1\f51\fs15\b\qc incorporation or organization)\cell\pard\plain\intbl\cf1\f51\fs15\b\qc (I.R.S. Employer\par\pard\plain\intbl\cf1\f51\fs15\b\qc Identification No.)\cell{
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\pard\plain\intbl\cf1\f51\fs17\b\qc Baarerstrasse 14
\par\pard\plain\intbl\fs16\pard\plain\intbl\cf1\f51\fs17\b\qc 6300 Zug, Switzerland\cell\pard\plain\intbl\cf1\f51\fs17\b\qc Not Applicable\cell{
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\pard\plain\intbl\cf1\f51\fs15\b\qc (Address of principal executive offices)\cell\pard\plain\intbl\cf1\f51\fs15\b\qc (Zip Code)\cell{
{\trowd\clvertalb\cellx5400\clvertalb\cellx10800\trrh186\row}}}\pard\plain\sb44\cf1\f51\fs17\b\qc Registrant\u8217?s telephone number, including area code: +41 (0)41 561 32 77\par\pard\plain\brdrb\brdrs\li880\ri880\sa22\cf1\f51\fs4\qc \~\par\pard\plain\sb44\fi528\cf1\f51\fs17\qc Securities registered pursuant to Section\~12(b) of the Act:\par\pard\plain\cf1\f51\fs4\ql \~\par\pard\plain\fi528\cf1\f51\fs4\ql \~
\par\pard\plain
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\pard\plain\intbl\brdrb\brdrs\cf1\f51\fs17\qc Common shares, nominal value CHF 0.03 per share\cell\pard\plain\intbl\cf1\f51\fs17\ql \~\cell\pard\plain\intbl\brdrb\brdrs\cf1\f51\fs17\qc The Nasdaq Global Market\cell{
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\pard\plain\intbl\li220\fi-220\cf1\f51\fs14\b\qc Title of each class\cell\pard\plain\intbl\cf1\f51\fs14\b\ql \~\cell\pard\plain\intbl\cf1\f51\fs14\b\qc Name of each exchange on which registered\cell{
{\trowd\cellx4885\cellx6114\cellx10800\trrh173\row}}}\pard\plain\sb44\fi528\cf1\f51\fs17\ql Securities registered pursuant to Section\~12(g) of the Act:\plain\cf1\f51\fs17\b\ql None\par\pard\plain\sb44\fi528\cf1\f51\fs17\ql Indicate by check mark if the Registrant is a well-known seasoned issuer, as defined in Rule\~405 of the Securities\plain\cf1\f51\fs17\ql Act.\~\~\~\~YES\~\~\u9744?\~\~\~\~NO\~\~\u9746?\par\pard\plain\sb44\fi528\cf1\f51\fs17\ql Indicate by check mark if the Registrant is not required to file reports pursuant to Section\~13 or 15(d) of the Act.\~\~\~\~YES\~\~\u9744?\~\~\~\~NO\~\~\u9746?\par\pard\plain\sb44\fi528\cf1\f51\fs17\ql Indicate by check mark whether the Registrant: (1)\~has filed all reports required to be filed by Section\~13 or 15(d) of the Securities Exchange\plain\cf1\f51\fs17\ql Act of 1934 during the preceding 12\~months (or for such shorter period that the Registrant was required to file such reports), and (2)\~has been subject\plain\cf1\f51\fs17\ql to such filing requirements for the past 90\~days.\~\~\~\~YES\~\~\u9746?\~\~\~\~NO\~\~\u9744?\par\pard\plain\sb44\fi528\cf1\f51\fs17\ql Indicate by check mark whether the Registrant has submitted electronically and posted on its corporate Web site, if any, every Interactive Data\plain\cf1\f51\fs17\ql File required to be submitted and posted pursuant to Rule\~405 of Regulation\~S-T (\u167?232.405 of this chapter) during the preceding 12\~months (or\plain\cf1\f51\fs17\ql for such shorter period that the Registrant was required to submit and post such files).\~\~\~\~YES\~\~\u9746?\~\~\~\~NO\~\~\u9744?\par\pard\plain\sb44\fi528\cf1\f51\fs17\ql Indicate by check mark if disclosure of delinquent filers pursuant to Item\~405 of Regulation\~S-K (\u167?229.405) is not contained herein, and\plain\cf1\f51\fs17\ql will not be contained, to the best of Registrant\u8217?s knowledge, in definitive proxy or information statements incorporated by reference in Part\~III of\plain\cf1\f51\fs17\ql this Form\~10-K or any amendment to this Form\~10-K.\~\~\u9746?\~\~\par\pard\plain\sb44\fi528\cf1\f51\fs17\ql Indicate by check mark whether the Registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, or a smaller reporting\plain\cf1\f51\fs17\ql company. See the definition of \u8220?large accelerated filer\u8221?, \u8220?accelerated filer\u8221?, and \u8220?smaller reporting company\u8221? in\plain\cf1\f51\fs17\ql Rule\~12b-2 of the Exchange Act. (Check one):\par\pard\plain\cf1\f51\fs4\ql \~
\par\pard\plain
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{\trowd\cellx1722\cellx1784\cellx7913\cellx8020\cellx10166\cellx10228\cellx10800\trrh210
\pard\plain\intbl\cf1\f51\fs17\ql \~\cell\pard\plain\intbl\cf1\f51\fs17\ql \~\cell\pard\plain\intbl\cf1\f51\fs17\ql \~\cell\pard\plain\intbl\cf1\f51\fs17\ql \~\cell\pard\plain\intbl\cf1\f51\fs17\ql Emerging growth company\cell\pard\plain\intbl\cf1\f51\fs17\ql \~\cell\pard\plain\intbl\cf1\f51\fs17\ql \u9746?\cell{
{\trowd\cellx1722\cellx1784\cellx7913\cellx8020\cellx10166\cellx10228\cellx10800\trrh210\row}}}\pard\plain\cf1\f51\fs4\ql \~\par\pard\plain\fi528\cf1\f51\fs17\ql If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying\plain\cf1\f51\fs17\ql with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. \u9746?\par\pard\plain\sb44\fi528\cf1\f51\fs17\ql Indicate by check mark whether the Registrant is a shell company (as defined in Rule\~12b-2 of the Exchange\plain\cf1\f51\fs17\ql Act).\~\~\~\~YES\~\~\u9744?\~\~\~\~NO\~\~\u9746?\par\pard\plain\sb44\fi528\cf1\f51\fs17\ql As of June 30, 2017, the aggregate market value of the Common Stock held by non-affiliates of the registrant was approximately $605.5\plain\cf1\f51\fs17\ql million, based on the closing price of the registrant\u8217?s common stock on June 30, 2017.\par\pard\plain\sb44\fi528\cf1\f51\fs17\ql As of February\~28, 2018, 46,976,000 common shares were outstanding.\par\pard\plain\cf1\f51\fs4\b\qc \~\par\pard\plain\cf1\f51\fs4\b\qc \~\par\pard\plain\cf1\f51\fs17\b\qc DOCUMENTS INCORPORATED BY REFERENCE\par\pard\plain\cf1\f51\fs4\ql \~\par\pard\plain\fi528\cf1\f51\fs17\ql Portions of the Registrant\u8217?s Definitive Proxy Statement relating to the Annual General Meeting of Shareholders for the year ended\plain\cf1\f51\fs17\ql December\~31, 2017, which the registrant intends to file with the Securities and Exchange Commission pursuant to Regulation 14A within 120 days\plain\cf1\f51\fs17\ql after the end of the registrant\u8217?s fiscal year ended December 31, 2017, are incorporated by reference into Part\~III of this Report.\par\pard\plain\brdrb\brdrs\sa22\cf1\f51\fs8\ql \~\par\pard\plain\cf1\f51\fs2\ql \~\par\pard\plain\cf1\f51\fs8\ql \~\par\pard\plain\cf1\f51\fs20\qc \~\par\pard\plain\sb264\cf1\f51\fs20\qc \~\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\cf1\f51\fs20\b\qc Table of Contents\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart part_1_2_1}{\*\bkmkend part_1_2_1}{\*\bkmkstart item_1_3_1}{\*\bkmkend item_1_3_1}
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\pard\plain\intbl\li132\cf1\f51\fs20\ql Item\~3.\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_3_legal_proceedings_1211666" }{\*\fldrslt\cf3\f51\fs20\ql Legal Proceedings}}\cell\pard\plain\intbl\cf1\f51\fs20\qr \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 79\cell{
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\pard\plain\intbl\li132\cf1\f51\fs20\ql Item\~4.\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_4_mine_safety_disclosures_1" }{\*\fldrslt\cf3\f51\fs20\ql Mine Safety Disclosures}}\cell\pard\plain\intbl\cf1\f51\fs20\qr \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 80\cell{
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\pard\plain\intbl\cf1\f51\fs20\b\ql PART\~II\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qr \~\cell\pard\plain\intbl\cf1\f51\fs20\qr \~\cell{
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\pard\plain\intbl\li132\cf1\f51\fs20\ql Item\~5.\cell\pard\plain\intbl\li264\fi-264\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\li264\ul{\field{\*\fldinst HYPERLINK \\l "item_5_market_for_registrants_co" }{\*\fldrslt\cf3\f51\fs20\ql Market for Registrant\u8217?s Common Equity, Related Stockholder Matters and Issuer}}\plain\intbl\li264\ul{\field{\*\fldinst HYPERLINK \\l "item_5_market_for_registrants_co" }{\*\fldrslt\cf3\f51\fs20\ql Purchases of Equity Securities}}\cell\pard\plain\intbl\cf1\f51\fs20\qr \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 81\cell{
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\pard\plain\intbl\li132\cf1\f51\fs20\ql Item\~6.\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_6_selected_financial_data_1" }{\*\fldrslt\cf3\f51\fs20\ql Selected Financial Data}}\cell\pard\plain\intbl\cf1\f51\fs20\qr \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 84\cell{
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\pard\plain\intbl\li132\cf1\f51\fs20\ql Item\~7.\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_7_managements_discussion_an" }{\*\fldrslt\cf3\f51\fs20\ql Management\u8217?s Discussion and Analysis of Financial Condition and Results of Operations}}\cell\pard\plain\intbl\cf1\f51\fs20\qr \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 85\cell{
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\pard\plain\intbl\li132\cf1\f51\fs20\ql Item\~7A.\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_7a_quantitative_qualitative" }{\*\fldrslt\cf3\f51\fs20\ql Quantitative and Qualitative Disclosures About Market Risk}}\cell\pard\plain\intbl\cf1\f51\fs20\qr \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 95\cell{
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\pard\plain\intbl\li132\cf1\f51\fs20\ql Item\~8.\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_8_financial_statements_supp" }{\*\fldrslt\cf3\f51\fs20\ql Financial Statements and Supplementary Data}}\cell\pard\plain\intbl\cf1\f51\fs20\qr \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 96\cell{
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\pard\plain\intbl\li132\cf1\f51\fs20\ql Item\~9.\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_9_changes_in_disagreements_" }{\*\fldrslt\cf3\f51\fs20\ql Changes in and Disagreements with Accountants on Accounting and Financial Disclosure}}\cell\pard\plain\intbl\cf1\f51\fs20\qr \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 96\cell{
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\pard\plain\intbl\li132\cf1\f51\fs20\ql Item\~9A.\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_9a_controls_procedures_1211" }{\*\fldrslt\cf3\f51\fs20\ql Controls and Procedures}}\cell\pard\plain\intbl\cf1\f51\fs20\qr \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 96\cell{
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\pard\plain\intbl\li132\cf1\f51\fs20\ql Item\~9B.\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_9b_or_information_12116663" }{\*\fldrslt\cf3\f51\fs20\ql Other Information}}\cell\pard\plain\intbl\cf1\f51\fs20\qr \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 97\cell{
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\pard\plain\intbl\cf1\f51\fs20\b\ql PART\~III\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qr \~\cell\pard\plain\intbl\cf1\f51\fs20\qr \~\cell{
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\pard\plain\intbl\li132\cf1\f51\fs20\ql Item\~10.\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_10_directors_executive_fice" }{\*\fldrslt\cf3\f51\fs20\ql Directors, Executive Officers and Corporate Governance}}\cell\pard\plain\intbl\cf1\f51\fs20\qr \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 98\cell{
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\pard\plain\intbl\li132\cf1\f51\fs20\ql Item\~11.\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_11_executive_compensation_1" }{\*\fldrslt\cf3\f51\fs20\ql Executive Compensation}}\cell\pard\plain\intbl\cf1\f51\fs20\qr \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 98\cell{
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\pard\plain\intbl\li132\cf1\f51\fs20\ql Item\~12.\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_12_security_ownership_certa" }{\*\fldrslt\cf3\f51\fs20\ql Security Ownership of Certain Beneficial Owners and Management and Related Stockholder}}\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_12_security_ownership_certa" }{\*\fldrslt\cf3\f51\fs20\ql Matters}}\cell\pard\plain\intbl\cf1\f51\fs20\qr \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 98\cell{
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\pard\plain\intbl\li132\cf1\f51\fs20\ql Item\~13.\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_13_certain_relationships_re" }{\*\fldrslt\cf3\f51\fs20\ql Certain Relationships and Related Transactions, and Director Independence}}\cell\pard\plain\intbl\cf1\f51\fs20\qr \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 98\cell{
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\pard\plain\intbl\li132\cf1\f51\fs20\ql Item\~14.\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_14_principal_accounting_fee" }{\*\fldrslt\cf3\f51\fs20\ql Principal Accounting Fees and Services}}\cell\pard\plain\intbl\cf1\f51\fs20\qr \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 98\cell{
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{\trowd\clshdng100\clcfpat7\clcbpat7\cellx1473\clshdng100\clcfpat7\clcbpat7\cellx1818\clshdng100\clcfpat7\clcbpat7\cellx10168\clshdng100\clcfpat7\clcbpat7\cellx10273\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx10800\trrh264\row}}}\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb264\cf1\f51\fs20\qc i\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\fi528\cf1\f51\fs20\i\ql Throughout this Annual Report on Form 10-K, the \u8220?Company,\u8221? \u8220?CRISPR,\u8221? \u8220?CRISPR\plain\cf1\f51\fs20\i\ql Therapeutics,\u8221? \u8220?we,\u8221? \u8220?us,\u8221? and \u8220?our,\u8221? except where the context requires\plain\cf1\f51\fs20\i\ql otherwise, refer to CRISPR Therapeutics AG and its consolidated subsidiaries, and \u8220?our board of directors\u8221? refers\plain\cf1\f51\fs20\i\ql to the board of directors of CRISPR Therapeutics AG.\par\pard\plain\sb396\cf1\f51\fs20\b\ql Special Note Regarding Forward-Looking Statements and Industry Data\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql This Annual Report on Form 10-K contains forward-looking statements regarding, among other things, our future\plain\cf1\f51\fs20\ql discovery and development efforts, our future operating results and financial position, our business strategy, and other objectives\plain\cf1\f51\fs20\ql for our operations. The words \u8220?anticipate,\u8221? \u8220?believe,\u8221? \u8220?intend,\u8221? \u8220?expect,\u8221?\plain\cf1\f51\fs20\ql \u8220?may,\u8221? \u8220?estimate,\u8221? \u8220?predict,\u8221? \u8220?project,\u8221? \u8220?potential\u8221? and similar\plain\cf1\f51\fs20\ql expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these\plain\cf1\f51\fs20\ql identifying words. We have based these forward-looking statements largely on our current expectations and projections about\plain\cf1\f51\fs20\ql future events and financial trends that we believe may affect our business, financial condition and results of operations. There are\plain\cf1\f51\fs20\ql a number of important risks and uncertainties that could cause our actual results to differ materially from those indicated by\plain\cf1\f51\fs20\ql forward-looking statements. We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking\plain\cf1\f51\fs20\ql statements, and you should not place undue reliance on our forward-looking statements. Actual results or events could differ\plain\cf1\f51\fs20\ql materially from the plans, intentions and expectations disclosed in the forward-looking statements we make. We have included\plain\cf1\f51\fs20\ql important factors in the cautionary statements included in this Annual Report on Form 10-K, particularly in the section entitled\plain\cf1\f51\fs20\ql \u8220?Risk Factors\u8221? in Part I that could cause actual results or events to differ materially from the forward-looking\plain\cf1\f51\fs20\ql statements that we make. Our forward-looking statements do not reflect the potential impact of any future acquisitions, mergers,\plain\cf1\f51\fs20\ql dispositions, joint ventures or investments that we may make.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql You should read this Annual Report on Form 10-K and the documents that we have filed as exhibits to this Annual Report\plain\cf1\f51\fs20\ql on Form\~10-K completely and with the understanding that our actual future results may be materially different from what we\plain\cf1\f51\fs20\ql expect. The forward-looking statements contained in this Annual Report on Form 10-K are made as of the date of this Annual\plain\cf1\f51\fs20\ql Report on\~Form\~10-K, and we do not assume any obligation to update any forward-looking statements, whether as a result of\plain\cf1\f51\fs20\ql new information, future events or otherwise, except as required by applicable law.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql This Annual Report on Form 10-K includes statistical and other industry and market data, which we obtained from our\plain\cf1\f51\fs20\ql own internal estimates and research, as well as from industry and general publications and research, surveys, and studies\plain\cf1\f51\fs20\ql conducted by third parties. Industry publications, studies, and surveys generally state that they have been obtained from sources\plain\cf1\f51\fs20\ql believed to be reliable, although they do not guarantee the accuracy or completeness of such information. While we believe that\plain\cf1\f51\fs20\ql each of these studies and publications is reliable, we have not independently verified market and industry data from\plain\cf1\f51\fs20\ql third\u8209?party sources. While we believe our internal company research is reliable and the market definitions are appropriate,\plain\cf1\f51\fs20\ql neither such research nor these definitions have been verified by any independent source.\par\pard\plain\sb264\fi528\cf1\f51\fs24\ql \~\par\pard\plain\sb264\cf1\f51\fs20\qc ii\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart part_1_2_2}{\*\bkmkend part_1_2_2}{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}{\*\bkmkstart part_i_12116663}{\*\bkmkend part_i_12116663}\par\pard\plain\cf1\f51\fs20\b\qc PART I{\*\bkmkstart item_1_3_2}{\*\bkmkend item_1_3_2}{\*\bkmkstart item_1_business_12116663}{\*\bkmkend item_1_business_12116663}\par\pard\plain\sb264\cf1\f51\fs20\b\ql Item 1. Business.\par\pard\plain\sb264\cf1\f51\fs20\b\qc BUSINESS\par\pard\plain\sb264\cf1\f51\fs20\b\ql Overview\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We are a leading gene editing company focused on the development of CRISPR/Cas9-based therapeutics. CRISPR/Cas9\plain\cf1\f51\fs20\ql stands for\plain\cf1\f51\fs20\ql C\plain\cf1\f51\fs20\ql lustered,\plain\cf1\f51\fs20\ql R\plain\cf1\f51\fs20\ql egularly\plain\cf1\f51\fs20\ql I\plain\cf1\f51\fs20\ql nterspaced\plain\cf1\f51\fs20\ql S\plain\cf1\f51\fs20\ql hort\plain\cf1\f51\fs20\ql P\plain\cf1\f51\fs20\ql alindromic\plain\cf1\f51\fs20\ql R\plain\cf1\f51\fs20\ql epeats (CRISPR)\plain\cf1\f51\fs20\ql A\plain\cf1\f51\fs20\ql ssociated protein-9 and is a revolutionary\plain\cf1\f51\fs20\ql technology for gene editing, the process of precisely altering specific sequences of genomic DNA. We are applying this\plain\cf1\f51\fs20\ql technology to potentially treat a broad set of both rare and common diseases by disrupting, correcting or regulating\plain\cf1\f51\fs20\ql disease-related genes. We believe that our scientific expertise, together with our gene editing approach, may enable an entirely\plain\cf1\f51\fs20\ql new class of highly effective and potentially curative treatments for patients for whom current biopharmaceutical approaches have\plain\cf1\f51\fs20\ql had limited success. Our most advanced programs target beta-thalassemia and sickle cell disease, two hemoglobinopathies that\plain\cf1\f51\fs20\ql have high unmet medical need.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The use of CRISPR/Cas9 for gene editing was derived from a naturally occurring viral defense mechanism in bacteria and\plain\cf1\f51\fs20\ql has been described by leading scientific journals as a breakthrough technology. The application of CRISPR/Cas9 for gene editing\plain\cf1\f51\fs20\ql was co-invented by one of our scientific founders, Dr. Emmanuelle Charpentier, a director of the Max-Planck Institute for\plain\cf1\f51\fs20\ql Infection Biology in Berlin. Dr.\~Charpentier and her collaborators published work elucidating the mechanism by which the Cas9\plain\cf1\f51\fs20\ql endonuclease, a key component of CRISPR/Cas9, can be programmed to cut double-stranded DNA at specific locations. We\plain\cf1\f51\fs20\ql have acquired rights to the foundational intellectual property encompassing CRISPR/Cas9 and related technologies from\plain\cf1\f51\fs20\ql Dr.\~Charpentier, and continue to strengthen our intellectual property estate through our own research and additional in-licensing\plain\cf1\f51\fs20\ql efforts, furthering our leadership in the development of CRISPR/Cas9-based therapeutics.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Our product development and partnership strategies are designed to exploit the full potential of the CRISPR/Cas9 platform\plain\cf1\f51\fs20\ql while maximizing the probability of successfully developing our product candidates. We are pursuing a two-pronged product\plain\cf1\f51\fs20\ql development strategy using both\plain\cf1\f51\fs20\i\ql ex vivo\plain\cf1\f51\fs20\ql and\plain\cf1\f51\fs20\i\ql in vivo\plain\cf1\f51\fs20\ql approaches. Our most advanced product candidate, referred to as CTX001,\plain\cf1\f51\fs20\ql targets sickle cell disease and beta-thalassemia with an\~\plain\cf1\f51\fs20\i\ql ex vivo\~\plain\cf1\f51\fs20\ql approach whereby cells are harvested from a patient, treated with\plain\cf1\f51\fs20\ql a CRISPR/Cas9-based therapeutic and reintroduced into the patient. In December 2017, we filed clinical trial applications\plain\cf1\f51\fs20\ql (CTAs) for CTX001 in major European countries for beta-thalassemia and plan to initiate clinical trials during 2018. We have\plain\cf1\f51\fs20\ql chosen to conduct our lead programs in these two hemoglobinopathies given the relative ease of editing genes\plain\cf1\f51\fs20\i\ql ex vivo\plain\cf1\f51\fs20\ql , the\plain\cf1\f51\fs20\ql significant unmet medical need associated with sickle cell disease and beta-thalassemia, and the well-understood genetics of\plain\cf1\f51\fs20\ql these diseases. Drawing from the\plain\cf1\f51\fs20\i\ql ex vivo\plain\cf1\f51\fs20\ql gene editing expertise gained through our lead programs, we are advancing\plain\cf1\f51\fs20\ql immuno-oncology cell therapy programs starting with CTX101, a healthy donor-derived gene-edited allogeneic CAR-T therapy\plain\cf1\f51\fs20\ql targeting CD19-positive malignancies. In addition, we have two earlier stage allogeneic CAR-T programs targeting B-Cell\plain\cf1\f51\fs20\ql maturation antigen, or BCMA and CD70. Beyond our\plain\cf1\f51\fs20\i\ql ex vivo\plain\cf1\f51\fs20\ql programs, we are also pursuing select\plain\cf1\f51\fs20\i\ql in vivo\plain\cf1\f51\fs20\ql applications, whereby\plain\cf1\f51\fs20\ql the CRISPR/Cas9-based therapeutic is delivered directly to target cells within the human body. Our initial\plain\cf1\f51\fs20\i\ql in vivo\plain\cf1\f51\fs20\ql applications\plain\cf1\f51\fs20\ql will leverage well-established delivery technologies for gene-based therapeutics.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Given the numerous potential therapeutic applications for CRISPR/Cas9, we have partnered strategically to broaden the\plain\cf1\f51\fs20\ql indications we can pursue and accelerate development of programs by accessing specific technologies and/or disease-area\plain\cf1\f51\fs20\ql expertise. In particular, we established a joint venture, called Casebia Therapeutics LLP, with Bayer HeathCare and its\plain\cf1\f51\fs20\ql subsidiaries, or Bayer, in which we have a 50% interest, and a collaboration agreement with Vertex Pharmaceuticals Incorporated,\plain\cf1\f51\fs20\ql or Vertex, in order to pursue specific indications where these companies have outstanding and distinctive capabilities. In\plain\cf1\f51\fs20\ql December 2017, we entered into a joint development and commercialization agreement with Vertex to co-develop and\plain\cf1\f51\fs20\ql co-commercialize CTX001 as part of our existing collaboration. The significant resource commitments by our partners\plain\cf1\f51\fs20\ql underscore the potential of our platform, as well as their dedication to developing transformative CRISPR/Cas9-based\plain\cf1\f51\fs20\ql therapeutics.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Our mission is to create transformative gene-based medicines for serious human diseases. We believe that our highly\plain\cf1\f51\fs20\ql experienced team, together with our scientific expertise, product development strategy, partnerships and intellectual property\plain\cf1\f51\fs20\ql position us as a leader in the development of CRISPR/Cas9-based therapeutics.\par\pard\plain\sb396\cf1\f51\fs20\b\ql Gene Editing Background{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql There are thousands of diseases caused by aberrant DNA sequences. Traditional small molecule and biologic therapies have\plain\cf1\f51\fs20\ql had limited success in treating many of these diseases because they fail to address the underlying genetic causes. Newer\plain\cf1\f51\fs20\ql approaches such as RNA therapeutics and viral gene therapy more directly target the genes related to disease, but each has clear\plain\cf1\f51\fs20\ql limitations. RNA-based therapies, such as mRNA and siRNA, face challenges with repeat dosing and related toxicities.\plain\cf1\f51\fs20\ql Non-integrating viral gene\par\pard\plain\sb264\cf1\f51\fs20\qc 1\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb132\cf1\f51\fs20\ql therapy platforms, such as adeno-associated virus, or AAV, may have limited durability because they do not permanently change\plain\cf1\f51\fs20\ql the genome and have limited efficacy upon re-administration due to resulting immune responses. Integrating viral gene therapy\plain\cf1\f51\fs20\ql platforms, such as lentivirus, permanently alter the genome but do so randomly, which leads to the potential for undesirable\plain\cf1\f51\fs20\ql mutations. Additionally, cells may recognize the transduced genes as foreign and respond by reducing their expression, limiting\plain\cf1\f51\fs20\ql their efficacy. Thus, while our understanding of genetic diseases has increased tremendously since the mapping of the human\plain\cf1\f51\fs20\ql genome, our ability to treat them effectively has been limited.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We believe gene editing has the potential to enable a next generation of therapeutics and provide curative solutions to many\plain\cf1\f51\fs20\ql genetic diseases through precise gene modification. The process of gene editing involves precisely altering DNA sequences within\plain\cf1\f51\fs20\ql the genomes of cells using enzymes to cut the DNA at specific locations. After a cut is made, natural cellular processes repair\plain\cf1\f51\fs20\ql the DNA to either silence or correct undesirable sequences, potentially reversing their negative effects. Importantly, because the\plain\cf1\f51\fs20\ql genome itself is modified in this process, the change is permanent in the patient.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Earlier generations of gene-editing technologies, such as zinc finger nucleases (ZFNs), transcription-activator like effector\plain\cf1\f51\fs20\ql nucleases (TALENs) and meganucleases, rely on engineered protein-DNA interactions. While these systems were an important\plain\cf1\f51\fs20\ql first step to demonstrate the potential of gene editing, their development has been challenging in practice due to the complexity\plain\cf1\f51\fs20\ql of engineering protein-DNA interactions. In contrast, CRISPR/Cas9 is guided by RNA-DNA interactions, which are more\plain\cf1\f51\fs20\ql predictable and straightforward to engineer and apply.\par\pard\plain\sb396\cf1\f51\fs20\b\ql The CRISPR/Cas9 Technology\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql CRISPR/Cas9 evolved as a naturally occurring defense mechanism that protects bacteria against viral infections.\plain\cf1\f51\fs20\ql Dr.\~Emmanuelle Charpentier and her collaborators elucidated this mechanism and developed ways to adapt and simplify it for use\plain\cf1\f51\fs20\ql in gene editing. The CRISPR/Cas9 technology they described consists of three basic components:\plain\cf1\f51\fs20\ql C\plain\cf1\f51\fs20\ql RISPR-\plain\cf1\f51\fs20\ql A\plain\cf1\f51\fs20\ql ssociated protein 9,\plain\cf1\f51\fs20\ql or Cas9, CRISPR RNA, or crRNA, and trans-activating CRISPR RNA, or tracrRNA. Cas9, in combination with these two RNA\plain\cf1\f51\fs20\ql molecules, is described as \u8220?molecular scissors\u8221? that can make specific cuts and edits in selected double-stranded\plain\cf1\f51\fs20\ql DNA.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Dr.\~Emmanuelle Charpentier and her collaborators further simplified the system for use in gene editing by combining the\plain\cf1\f51\fs20\ql crRNA and tracrRNA into a single RNA molecule called a guide RNA. The guide RNA binds to Cas9 and can be programmed\plain\cf1\f51\fs20\ql to direct the Cas9 enzyme to a specific DNA sequence based on Watson-Crick base pairing rules. The CRISPR/Cas9 technology\plain\cf1\f51\fs20\ql can be used to make cuts in DNA at specific sites of targeted genes, providing a powerful tool for developing gene editing based\plain\cf1\f51\fs20\ql therapeutics.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Once the DNA is cut, the cell uses naturally occurring DNA repair mechanisms to rejoin the cut ends. If a new DNA\plain\cf1\f51\fs20\ql template with the correct sequence has been delivered to the cell prior to the time the DNA is cut, it will be incorporated, leading\plain\cf1\f51\fs20\ql to a correction of the targeted gene, which we refer to as gene correction. Alternatively, if no DNA template is present, the cell\plain\cf1\f51\fs20\ql will rejoin the two cut ends in a way that will likely lead to the disruption and inactivation of the gene, which we refer to as\plain\cf1\f51\fs20\ql gene disruption.\par\pard\plain\sb264\cf1\f51\fs20\qc 2\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql CRISPR/Cas9 can also be adapted to regulate the activity of an existing gene without modifying the actual DNA sequence,\plain\cf1\f51\fs20\ql which we refer to as gene regulation. This is accomplished using a catalytically inactive form of the Cas9 enzyme that can be\plain\cf1\f51\fs20\ql directed to bind specific DNA sequences without cutting. By linking this inactive Cas9 to proteins that regulate gene function, the\plain\cf1\f51\fs20\ql activity of specific genes can be either up or downregulated.\par\pard\plain\sb264\cf1\f51\fs20\b\qc CRISPR/Cas9 gene editing\par\pard\plain\cf1\f51\fs24\ql \~\par\qc{\*\shppict{\pict\pngblip\picw605\pich270\picscalex74\picscaley74\bliptag-9728958103
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\par\pard\plain\sb264\cf1\f51\fs24\qc \~\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb44\fi528\cf1\f51\fs20\ql We believe that CRISPR/Cas9 is a versatile technology that can be used to either disrupt, correct or regulate genes. We\plain\cf1\f51\fs20\ql intend to take advantage of the versatility and modularity of the CRISPR/Cas9 system to adapt and rapidly customize individual\plain\cf1\f51\fs20\ql components for specific disease applications. Consequently, we believe that CRISPR/Cas9 may form the basis of a new class of\plain\cf1\f51\fs20\ql therapeutics with the potential to treat both rare and common diseases.\par\pard\plain\sb264\cf1\f51\fs20\qc 3\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb396\cf1\f51\fs20\b\ql Our Pipeline\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql The following table summarizes the status of our product development pipeline:\par\pard\plain\cf1\f51\fs20\ql \~\par\qc{\*\shppict{\pict\pngblip\picw672\pich432\picscalex74\picscaley74\bliptag-9728958103
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\par\pard\plain\li44\sb396\cf1\f51\fs20\b\ql Ex Vivo\plain\li44\cf1\f51\fs20\b\i\ql Hematopoietic Programs\par\pard\plain\li44\sb132\cf1\f51\fs20\i\ql Background\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We are primarily utilizing\plain\cf1\f51\fs20\i\ql ex vivo\plain\cf1\f51\fs20\ql approaches to treat diseases related to the hematopoietic system, which is the system of\plain\cf1\f51\fs20\ql organs and tissues, such as bone marrow, the spleen and lymph nodes, involved in the production of blood. Today, many of the\plain\cf1\f51\fs20\ql hematopoietic system diseases we are targeting are treated with allogeneic hematopoietic stem cell transplants, or allo-HSCT. In\plain\cf1\f51\fs20\ql performing allo-HSCT, physicians replace a patient\u8217?s blood-forming cells that contain the defective gene with cells\plain\cf1\f51\fs20\ql obtained from a different person that contain the normal gene. Unfortunately, not all patients are able to be matched with suitable\plain\cf1\f51\fs20\ql donors. Patients who do undergo allo-HSCT face a high risk of complications such as infections related to immunosuppression,\plain\cf1\f51\fs20\ql transplant rejection and graft-versus-host disease, where\~immune cells in the transplanted tissue (the graft) recognize the recipient\plain\cf1\f51\fs20\ql (the host) as \u8220?foreign\u8221? and begin to attack the host\u8217?s cells.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In contrast to allo-HSCT, our approach harvests stem cells directly from the patient, edits the defective gene\plain\cf1\f51\fs20\i\ql ex vivo\plain\cf1\f51\fs20\ql , and\plain\cf1\f51\fs20\ql reintroduces those same cells back into the patient. We believe this\plain\cf1\f51\fs20\i\ql ex vivo\plain\cf1\f51\fs20\ql gene editing approach, which uses the patient\u8217?s\plain\cf1\f51\fs20\ql own cells, may provide better results than allo-HSCT.\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql Our Lead Programs\u8212?Hemoglobinopathies\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Hemoglobinopathies are a diverse group of inherited blood disorders that result from variations in the synthesis or structure\plain\cf1\f51\fs20\ql of hemoglobin. Our lead programs in hemoglobinopathies, for which we have partnered with Vertex, aim to develop a single,\plain\cf1\f51\fs20\ql potentially transformative CRISPR/Cas9-based therapy to treat both beta-thalassemia and sickle cell disease, or SCD. These\plain\cf1\f51\fs20\ql diseases are caused by mutations in the gene encoding the beta globin protein. Beta globin is an essential component of\plain\cf1\f51\fs20\ql hemoglobin, a protein in red blood cells that delivers oxygen and removes carbon dioxide throughout the body. Several factors\plain\cf1\f51\fs20\ql make these attractive lead indications, including: (i)\~high unmet medical need, (ii)\~compelling market potential,\plain\cf1\f51\fs20\ql (iii)\~well-understood genetics and (iv)\~the ability to employ an\plain\cf1\f51\fs20\i\ql ex vivo\plain\cf1\f51\fs20\ql gene disruption strategy.\par\pard\plain\sb264\cf1\f51\fs20\qc 4\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql Beta-thalassemia\par\pard\plain\li44\sb132\cf1\f51\fs20\i\ql Overview\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Beta-thalassemia is a blood disorder that is associated with a reduction in the production of hemoglobin. This disease is\plain\cf1\f51\fs20\ql caused by mutations that give rise to the insufficient expression of the beta globin protein, which can lead to symptoms related\plain\cf1\f51\fs20\ql not only to the lack of hemoglobin, but also to the buildup of unpaired alpha globin proteins in red blood cells. The severity of\plain\cf1\f51\fs20\ql symptoms associated with beta-thalassemia varies depending on the levels of functional beta globin present in the blood cells.\plain\cf1\f51\fs20\ql The unpaired alpha globin chains are toxic to red blood cells and reduce red blood cell lifespan. In the most severe cases,\plain\cf1\f51\fs20\ql described as beta-thalassemia major, functional beta globin is either completely absent or reduced, resulting in severe anemia. In\plain\cf1\f51\fs20\ql these patients, the bone marrow cannot keep pace with the destruction of red blood cells, and thus these patients require periodic\plain\cf1\f51\fs20\ql blood transfusions. While chronic blood transfusions can be effective at addressing symptoms, they often lead to iron overload,\plain\cf1\f51\fs20\ql progressive heart and liver failure, and eventually death. Patients with mild forms of beta-thalassemia may experience some mild\plain\cf1\f51\fs20\ql anemia or even be asymptomatic. The total worldwide incidence of beta-thalassemia is estimated to be 60,000 births annually,\plain\cf1\f51\fs20\ql the total prevalence in the United States and the European Union is estimated to be approximately 19,000 and there are over\plain\cf1\f51\fs20\ql 200,000 people worldwide who are alive and registered as receiving treatment for the disease.\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Limitations of current treatment options\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql The most common treatment for beta-thalassemia is chronic blood transfusions. Patients typically receive transfusions every\plain\cf1\f51\fs20\ql two to four weeks and chronic administration of blood often leads to elevated levels of iron in the body and can cause organ\plain\cf1\f51\fs20\ql damage over a relatively short period of time. Patients are often given iron chelators, or medicines to reduce iron levels in the\plain\cf1\f51\fs20\ql blood, which are associated with their own significant toxicities. Low adherence to this burdensome regime often results in death\plain\cf1\f51\fs20\ql by 30 years of age for patients with transfusion-dependent beta-thalassemia. The only potentially curative therapy for this\plain\cf1\f51\fs20\ql disease is allo-HSCT, but few patients elect to have this procedure given its associated morbidity and mortality. In developing\plain\cf1\f51\fs20\ql countries, where chronic transfusions are not available, most patients die in early childhood. We believe that our therapeutic\plain\cf1\f51\fs20\ql approach could offer a potentially curative treatment for this devastating disease.\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql Sickle Cell Disease\par\pard\plain\li44\sb132\cf1\f51\fs20\i\ql Overview\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql SCD is an inherited disorder of red blood cells resulting from a specific mutation in the beta globin gene that causes\plain\cf1\f51\fs20\ql abnormal red blood cell function. Under conditions of low oxygen concentration, the abnormal hemoglobin proteins aggregate\plain\cf1\f51\fs20\ql within the red blood cells causing them to become sickled in shape and inflexible. These sickled cells obstruct blood vessels,\plain\cf1\f51\fs20\ql restricting blood flow to organs, ultimately resulting in anemia, severe pain, infections, stroke, overall poor quality of life and\plain\cf1\f51\fs20\ql early death.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The worldwide incidence of SCD is estimated to be 300,000 births annually and there are 20 - 25\~million people\plain\cf1\f51\fs20\ql worldwide with the disease. In the United States, the total prevalence is estimated to be 100,000\~individuals.\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Limitations of current treatment options\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql As with beta-thalassemia, in regions where access to modern medical care is available, standard treatment for SCD\plain\cf1\f51\fs20\ql involves chronic blood transfusions, which has the same associated risks of iron overload and toxicities associated with chelation\plain\cf1\f51\fs20\ql therapy. Allo-HSCT is a second potential treatment option. While allo-HSCT provides the only potentially curative therapeutic\plain\cf1\f51\fs20\ql path for SCD, it is often avoided given the significant risk of transplant-related morbidity and mortality in these patients.\par\pard\plain\sb264\cf1\f51\fs20\qc 5\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql Our Gene Editing Approach\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Our therapeutic approach to treating beta-thalassemia and SCD employs gene editing to upregulate the expression of the\plain\cf1\f51\fs20\ql gamma globin protein, a hemoglobin subunit that is commonly present only in newborn infants. Hemoglobin that contains gamma\plain\cf1\f51\fs20\ql globin instead of beta globin protein is referred to as fetal hemoglobin, or HbF. In most individuals HbF disappears in infancy as\plain\cf1\f51\fs20\ql gamma globin is replaced by beta globin through naturally occurring suppression of the gamma globin gene. The symptoms of\plain\cf1\f51\fs20\ql beta-thalassemia and SCD typically do not manifest until several months after birth, when the levels of HbF have declined\plain\cf1\f51\fs20\ql considerably. Some patients with beta-thalassemia or SCD have elevated levels of HbF that persist into adulthood, a condition\plain\cf1\f51\fs20\ql known as hereditary persistence of fetal hemoglobin, or HPFH. Patients with HPFH are often asymptomatic, or experience much\plain\cf1\f51\fs20\ql milder forms of disease. This protective HPFH condition has been shown to result from specific changes to these patients\u8217?\plain\cf1\f51\fs20\ql genomic DNA, either in the region of the globin genes or in certain genetic regulatory elements that control the expression levels\plain\cf1\f51\fs20\ql of the globin genes.\par\pard\plain\sb264\cf1\f51\fs20\b\qc Relationship between level of HbF and morbidity in beta-thalassemia\par\pard\plain\sb44\cf1\f51\fs20\ql \~\par\qc{\*\shppict{\pict\pngblip\picw523\pich301\picscalex74\picscaley74\bliptag-9728958103
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\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql An alternative CRISPR/Cas9 approach to treating hemoglobinopathies would be to correct the mutated beta globin gene.\plain\cf1\f51\fs20\ql We have chosen the HbF upregulation strategy as our initial approach given the relative technical simplicity of the gene deletion\plain\cf1\f51\fs20\ql strategy involved, the ability of this strategy to counteract a wide variety of different beta globin mutations, and the absence of\plain\cf1\f51\fs20\ql symptoms in patients with high HbF levels.\par\pard\plain\sb264\cf1\f51\fs20\qc 6\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql Our Lead Hemoglobinopathies Product Candidate\u8212?CTX001\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Our lead product candidate, CTX001, uses CRISPR/Cas9 to mimic the high levels of HbF that occur naturally in HPFH\plain\cf1\f51\fs20\ql patients. To achieve this effect, CTX001 uses CRISPR/Cas9 to disrupt the erythroid specific enhancer of the BCL11A gene. This\plain\cf1\f51\fs20\ql gene encodes the BCL11A protein, a critical factor that keeps HbF levels low in most individuals. Disrupting the BCL11A\plain\cf1\f51\fs20\ql erythroid specific enhancer reduces BCL11A expression, thereby upregulating expression of gamma globin and increasing HbF\plain\cf1\f51\fs20\ql levels.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Our therapeutic approach involves isolating hematopoietic stem cells, or HSCs, which differentiate into red blood cells,\plain\cf1\f51\fs20\ql from a patient, treating those cells\plain\cf1\f51\fs20\i\ql ex vivo\plain\cf1\f51\fs20\ql with CRISPR/Cas9 to disrupt the BCL11A erythroid specific enhancer and\plain\cf1\f51\fs20\ql reintroducing the edited cells back into the patient. We believe that once reintroduced into the patient, these genetically modified\plain\cf1\f51\fs20\ql stem cells will give rise to red blood cells that contain high levels of HbF. In beta-thalassemia, elevating HbF may reduce the\plain\cf1\f51\fs20\ql toxicity of unpaired alpha globin chains, thereby increasing red blood cell lifespan. As a consequence, CTX001 may have the\plain\cf1\f51\fs20\ql potential to reduce or even eliminate the need for transfusions in these patients. In SCD, elevated HbF may prevent a cell from\plain\cf1\f51\fs20\ql sickling, and so achieving sufficiently high HbF in a majority of red blood cells could significantly reduce or eliminate the\plain\cf1\f51\fs20\ql symptoms associated with the disease.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In preclinical studies using CTX001, our CRISPR/Cas9 gene editing process demonstrated the ability to edit HSCs with\plain\cf1\f51\fs20\ql approximately 80% efficiency at clinical scale in a bulk population of cells.\par\pard\plain\sb264\cf1\f51\fs20\b\qc Editing efficiency at clinical scale in human CD34\plain\cf1\f51\fs18\b\qc\super +\plain\cf1\f51\fs20\b\qc cells\par\qc\sb264{\*\shppict{\pict\pngblip\picw250\pich269\picscalex74\picscaley74\bliptag-9728958103
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\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We observed this high editing efficiency across all stem cell subsets, including in long-term repopulating HSCs. After\plain\cf1\f51\fs20\ql erythroid differentiation, this editing resulted in HbF accounting for greater than 30% of total hemoglobin in edited cells,\plain\cf1\f51\fs20\ql compared to approximately 10% HbF in the control arm of the study. On a per cell basis, more than 90% of cells had\plain\cf1\f51\fs20\ql modifications at the desired location, with 76% of the cells having edits in both copies of the target gene, and 16% of the cells\plain\cf1\f51\fs20\ql having edits made on one copy of the target gene. We estimate that this editing rate results in HbF expression levels of greater\plain\cf1\f51\fs20\ql than 35% in cells that have edits on both copies of the target gene, and over 20% for cells edited at one gene.\par\pard\plain\sb264\cf1\f51\fs20\b\qc HbF ratio after editing and erythroid differentiation and estimated HbF expression at the cellular level\par\pard\plain\sb264\cf1\f51\fs20\qc 7\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\qc\sb264{\*\shppict{\pict\pngblip\picw720\pich271\picscalex74\picscaley74\bliptag-9728958103
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\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In preclinical mouse models designed to test the safety of CTX001, gene-edited HSCs maintained the ability to engraft\plain\cf1\f51\fs20\ql long-term and to differentiate into multiple lineages. Toxicology studies revealed no significant findings and no difference in the\plain\cf1\f51\fs20\ql biodistribution of edited cells compared to controls. Finally, no off-target activity was detectable for the CTX001 guide RNA\plain\cf1\f51\fs20\ql after assessing over 5,000 homology-based sites and over 2,000 homology-independent sites.\par\pard\plain\sb264\cf1\f51\fs20\b\qc CTX001 engraftment\plain\cf1\f51\fs20\b\i\qc in vivo\plain\cf1\f51\fs20\b\qc in mice\plain\cf1\f51\fs18\b\qc\super 1\par\qc\sb264{\*\shppict{\pict\pngblip\picw340\pich368\picscalex74\picscaley74\bliptag-9728958103
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\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In December 2017, we submitted CTAs in major European countries for CTX001 in beta-thalassemia.\~\~In March 2018, we\plain\cf1\f51\fs20\ql received approval of one such CTA and we expect to initiate clinical trials in Europe in 2018.\~\~We also expect to file an\plain\cf1\f51\fs20\ql investigational new drug, or IND, application with the United States Food and Drug Administration, or FDA, for CTX001 in\plain\cf1\f51\fs20\ql SCD during the first half of 2018. We have designed a single arm Phase 1/2 study in which we plan to enroll up to 30 adult\plain\cf1\f51\fs20\ql patients to assess the safety and efficacy of CTX001 in patients with beta-thalassemia.{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We believe our CRISPR/Cas9 gene editing strategy may have significant advantages over other gene therapies in\plain\cf1\f51\fs20\ql development for the treatment of hemoglobinopathies. For example, lentivirus-based treatments involve a random integration of\plain\cf1\f51\fs20\ql one or more copies\par\pard\plain\sb264\cf1\f51\fs20\qc 8\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb264\cf1\f51\fs20\ql of the globin gene throughout the genome. The expression levels of the newly introduced gene can vary depending on the exact\plain\cf1\f51\fs20\ql location of the DNA in the genome, leading to inconsistent and variable levels of expression. We believe our strategy may lead\plain\cf1\f51\fs20\ql to more uniform globin expression across a high percentage of cells. In addition, with each random lentiviral integration, a\plain\cf1\f51\fs20\ql mutation may be created, which may have an associated safety concern, including the potential to cause cancer. In contrast,\plain\cf1\f51\fs20\ql CRISPR/Cas9 targets a specific genomic site for editing, and we have detected no off-target activity for our CTX001 guide\plain\cf1\f51\fs20\ql RNA.\par\pard\plain\sb396\fi264\cf1\f51\fs20\b\i\ql Other Hematopoietic Programs\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql There are numerous additional diseases that are potentially treatable through\~\plain\cf1\f51\fs20\i\ql ex vivo\plain\cf1\f51\fs20\ql \~gene editing of the hematopoietic\plain\cf1\f51\fs20\ql system. We plan to apply the capabilities we are developing in hemoglobinopathies to treat other diseases, including Hurler\plain\cf1\f51\fs20\ql Syndrome and severe combined immunodeficiency disease, or SCID.\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql Hurler Syndrome\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Hurler syndrome is a type of mucopolysaccharide disease caused by a defective IDUA gene. The IDUA gene is responsible\plain\cf1\f51\fs20\ql for encoding alpha-L-iduronidase, an enzyme that breaks down large molecules called glycosaminoglycans, or GAGs, in the\plain\cf1\f51\fs20\ql lysosomes of cells. A defective IDUA gene results in a lack of alpha-L-iduronidase which leads to an accumulation of GAGs\plain\cf1\f51\fs20\ql and results in cellular dysfunction and severe clinical abnormalities. Patients with Hurler syndrome have a broad spectrum of\plain\cf1\f51\fs20\ql clinical problems including skeletal abnormalities, enlarged livers and spleens, and severe intellectual disability due to a lack of\plain\cf1\f51\fs20\ql this enzyme in the brain. Most patients experience a decline in intellectual development and often lose both vision and hearing as\plain\cf1\f51\fs20\ql the disease progresses. Without treatment, the average age at death is five years, and nearly all patients die by the age of ten. The\plain\cf1\f51\fs20\ql worldwide incidence of Hurler syndrome is approximately one in 100,000 births.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql There are two common approaches to treating mucopolysaccharide diseases: enzyme replacement therapy and allo-HSCT.\plain\cf1\f51\fs20\ql Enzyme replacement therapy, or ERT, does not adequately address the symptoms of Hurler syndrome because it cannot cross the\plain\cf1\f51\fs20\ql blood-brain barrier to address the severe neurologic symptoms associated with this disease. While allo-HSCT can be effective in\plain\cf1\f51\fs20\ql treating the disease, it is associated with significant morbidity and mortality, and not all patients are able to find suitable donors.\plain\cf1\f51\fs20\ql Even when a match is found, the delay between diagnosis and treatment often results in significant irreversible disease\plain\cf1\f51\fs20\ql progression. Our approach is to introduce a functional copy of the IDUA gene into a patient\u8217?s own hematopoietic cells\plain\cf1\f51\fs20\ql using\plain\cf1\f51\fs20\i\ql ex vivo\plain\cf1\f51\fs20\ql CRISPR/Cas9 gene editing, before returning them to the patient. We believe that using a patient\u8217?s own cells\plain\cf1\f51\fs20\ql rather than those from a donor will eliminate a potentially lengthy search for an appropriate donor, allowing us to intervene at an\plain\cf1\f51\fs20\ql earlier point and avoid the significant risks associated with allo-HSCT.\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql Severe Combined Immunodeficiency Disease\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Severe combined immunodeficiency disease, or SCID, is a disease in which the patient\u8217?s immune system is\plain\cf1\f51\fs20\ql compromised and cannot fight off infections. These patients are identified early in life because they often suffer from recurrent\plain\cf1\f51\fs20\ql severe respiratory infections, which can be life-threatening in the absence of a functioning immune system. There are multiple\plain\cf1\f51\fs20\ql underlying causes of SCID, and in one particularly severe form, a gene called RAG1 is mutated. Mutations in RAG1, a gene that\plain\cf1\f51\fs20\ql plays a critical role in the process of antibody generation, prevent normal development of the patient\u8217?s immune system,\plain\cf1\f51\fs20\ql resulting in an absence of B-cells, a type of white blood cell. The worldwide incidence of SCID is estimated to be one in 58,000\plain\cf1\f51\fs20\ql births, with the RAG1 mutation associated form accounting for approximately 15% of patients.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Currently, the only curative therapy for this potentially fatal disorder is allo-HSCT, which carries a high risk of\plain\cf1\f51\fs20\ql complications. Gene therapies for SCID insert copies of a replacement gene randomly into the genome, potentially resulting in\plain\cf1\f51\fs20\ql unwanted mutations. The risks associated with this type of gene therapy were underscored in a clinical trial for another variant of\plain\cf1\f51\fs20\ql SCID in which five out of twenty patients developed leukemia. We believe that the precise correction of the RAG1 gene with\plain\cf1\f51\fs20\ql CRISPR/Cas9 may bring benefit to these patients while minimizing the risk of leukemia associated with gene therapy.\plain\cf1\f51\fs20\ql Considering corrected cells proliferate faster than non-corrected cells, we believe that a small number of corrected cells\plain\cf1\f51\fs20\ql reintroduced into the patient could provide a therapeutic benefit and in time, compensate for the defective cells. With our\plain\cf1\f51\fs20\i\ql ex vivo\plain\cf1\f51\fs20\ql approach, we believe we can attain sufficient levels of correction to generate the desired therapeutic benefit. Our Casebia joint\plain\cf1\f51\fs20\ql venture with Bayer HealthCare will lead development of our SCID program, and leverage Bayer HealthCare\u8217?s expertise in\plain\cf1\f51\fs20\ql hematologic disorders.\par\pard\plain\sb396\cf1\f51\fs20\b\ql Ex Vivo\plain\cf1\f51\fs20\b\i\ql Immuno-Oncology Programs\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Over the past several years, interest in the oncology community has grown rapidly in the field of immuno-oncology, or\plain\cf1\f51\fs20\ql treatments that harness the immune system to attack cancer cells. Engineered immune cell therapy is one such approach, in which\plain\cf1\f51\fs20\ql immune system cells such as\~T-cells\~are genetically modified to enable them to recognize and attack cancerous cells.\par\pard\plain\sb264\cf1\f51\fs20\qc 9\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Engineered cell therapy has demonstrated encouraging results leading to two recent approvals for autologous\~CD19\~chimeric\plain\cf1\f51\fs20\ql antigen receptor\~T-cell,\~or\~CAR-T,\~products, and may become an entirely new class of oncology therapeutics; however, realizing\plain\cf1\f51\fs20\ql this full potential will require overcoming some key challenges. Most engineered cell therapies in development require unique\plain\cf1\f51\fs20\ql products to be created for each patient treated, an approach that has in the past proven challenging and cost prohibitive in the\plain\cf1\f51\fs20\ql field of oncology. Additionally, these versions of engineered cell therapies appear limited in their ability to treat solid tumors and\plain\cf1\f51\fs20\ql have demonstrated\~sub-optimal\~safety profiles.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We expect that the cellular engineering strategies that are ultimately successful in immuno-oncology will involve multiple\plain\cf1\f51\fs20\ql genetic modifications, an application for which we believe CRISPR/Cas9 will play a central role. While other gene editing\plain\cf1\f51\fs20\ql platforms could potentially be used for these purposes, CRISPR/Cas9 is particularly well-suited for multiplexed editing, which is\plain\cf1\f51\fs20\ql the modification and/or insertion of multiple genes within a single cell. Current gene editing techniques that require different\plain\cf1\f51\fs20\ql protein enzymes for each genetic modification may be limited in the number of edits they can make concurrently due to\plain\cf1\f51\fs20\ql efficiency, cytotoxicity, and/or manufacturing challenges. In contrast, CRISPR/Cas9 has the potential to efficiently make multiple\plain\cf1\f51\fs20\ql edits using a single Cas9 protein and multiple small guide RNA molecules. Given the important role we believe CRISPR/Cas9\plain\cf1\f51\fs20\ql will play in engineered cell therapy going forward we have thus far elected to wholly own all of our immune-oncology\plain\cf1\f51\fs20\ql programs.\~\~\par\pard\plain\sb396\cf1\f51\fs20\b\i\ql Our Lead Immuno-Oncology Product Candidate\u8212?CTX101\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Our lead immuno-oncology product candidate, CTX101, is a healthy-donor derived allogeneic\~CAR-T cell product\plain\cf1\f51\fs20\ql targeting\~CD19-positive malignancies, such as certain lymphomas and leukemias. A primary aim of CTX101 is to overcome the\plain\cf1\f51\fs20\ql inefficiency and cost of creating a unique product for each patient in a tumor type by treating many different patients from a\plain\cf1\f51\fs20\ql single batch, which we refer to as being an\~\u8220?off-the-shelf\u8221?\~therapy. To generate CTX101, we make three\plain\cf1\f51\fs20\ql modifications to\~T-cells\~taken from healthy donors using our CRISPR/Cas9 technology: (i)\~the T cell receptor, or TCR, is\plain\cf1\f51\fs20\ql eliminated to reduce the risk of graft versus host disease from the product, (ii)\~a\~CD19-directed CAR is inserted site-specifically\plain\cf1\f51\fs20\ql into the TCR gene and (iii)\~the class I major histocompatibility complex, MHC-I, is removed from the cell surface in order to\plain\cf1\f51\fs20\ql improve the persistence of the\~CAR-T\~cells in an\~\u8220?off-the-shelf\u8221?\~setting. We believe this approach will have\plain\cf1\f51\fs20\ql advantages over other allogeneic\~CAR-T\~products in development that semi-randomly insert the CAR using an integrating virus,\plain\cf1\f51\fs20\ql and do not include the MHC-I knockout to increase persistence. As shown in the figure below, we have demonstrated the ability\plain\cf1\f51\fs20\ql to perform the edits necessary to generate CTX101 at high efficiency, and that in preclinical testing CTX101 has comparable\plain\cf1\f51\fs20\ql cytotoxic activity to currently approved\~CD19 CAR-T\~products. We have transferred production of CTX101 to\plain\cf1\f51\fs20\ql a\~GMP-capable\~contract manufacturing organization (\u8220?CMO\u8221?) and are planning to file an IND for CTX101 by the\plain\cf1\f51\fs20\ql end of 2018.\par\pard\plain\sb264\cf1\f51\fs20\b\qc Efficient production of CTX101 via multiplexed editing and CTX101 cytotoxic activity\plain\cf1\f51\fs20\b\i\qc in vitro\par\qc\sb264{\*\shppict{\pict\pngblip\picw682\pich263\picscalex74\picscaley74\bliptag-9728958103
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\par\pard\plain\sb396\cf1\f51\fs20\b\i\ql Other Immuno-Oncology Programs\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Beyond CTX101, we are developing additional\~programs directed to other tumor targets including\~B-cell\~maturation\plain\cf1\f51\fs20\ql antigen, or BCMA, and\~CD70.\~These programs will leverage many of the capabilities and reagents developed for CTX101,\plain\cf1\f51\fs20\ql potentially enabling them to progress quickly into development.\par\pard\plain\sb264\cf1\f51\fs20\qc 10\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql BCMA has attractive properties for CAR-T cell therapy, namely expression on the surface of B-lineage cells, especially\plain\cf1\f51\fs20\ql the plasma cells involved in multiple myeloma, and absence from other tissues and cell types. As a result, BCMA has become a\plain\cf1\f51\fs20\ql promising target for autologous CAR-T cell therapy. We have tested multiple constructs\plain\cf1\f51\fs20\i\ql in vitro\plain\cf1\f51\fs20\ql and\plain\cf1\f51\fs20\i\ql in vivo\plain\cf1\f51\fs20\ql in order to select a\plain\cf1\f51\fs20\ql lead allogeneic CAR-T cell product candidate to progress into development.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql CD70 also shows properties that we believe make it a promising CAR-T cell target. A number of cancers express CD70,\plain\cf1\f51\fs20\ql including non-Hodgkin\u8217?s lymphoma, renal cell carcinoma, and glioblastoma, while normal tissues do not express or show\plain\cf1\f51\fs20\ql extremely limited expression of CD70. This target enables us to transition from hematological cancers, such as\plain\cf1\f51\fs20\ql non-Hodgkin\u8217?s lymphoma, to solid tumor cancers, such as renal cell carcinoma. In preclinical studies of an allogeneic\plain\cf1\f51\fs20\ql CAR-T cell product candidate directed against CD70, we observed promising anti-tumor activity, including the complete\plain\cf1\f51\fs20\ql eradication of tumors in a mouse model of renal cell carcinoma.\par\pard\plain\sb264\cf1\f51\fs20\b\qc Elimination of a subcutaneous A498 renal cell carcinoma model by allogeneic anti-CD70 CAR-T cells (CTX-CD70)\par\qc\sb264{\*\shppict{\pict\pngblip\picw524\pich351\picscalex74\picscaley74\bliptag-9728958103
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\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In these and future programs, we may use the multiplexing ability of CRISPR/Cas9 to introduce additional genetic edits to\plain\cf1\f51\fs20\ql improve the efficacy and safety profile of these products. Such edits could include the removal of checkpoint inhibitors or\plain\cf1\f51\fs20\ql introduction of safety elements. We continue to expand our multiplexing capabilities through platform development in order to\plain\cf1\f51\fs20\ql help us realize the full potential of engineered cell therapy in immuno-oncology across all tumor types, including solid tumors.\par\pard\plain\sb396\cf1\f51\fs20\b\i\ql In Vivo Programs\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql In parallel with our\plain\cf1\f51\fs20\i\ql ex vivo\plain\cf1\f51\fs20\ql programs, we are pursuing a number of\plain\cf1\f51\fs20\i\ql in vivo\plain\cf1\f51\fs20\ql indications, which will involve delivery of\plain\cf1\f51\fs20\ql CRISPR/Cas9-based therapeutics directly to tissues within the human body. Our initial\plain\cf1\f51\fs20\i\ql in vivo\plain\cf1\f51\fs20\ql applications will target the liver,\plain\cf1\f51\fs20\ql leveraging well-established delivery technologies. We have also begun optimizing delivery systems to target other organ systems,\plain\cf1\f51\fs20\ql including musculoskeletal and pulmonary.\par\pard\plain\sb396\cf1\f51\fs20\b\ql Liver Diseases\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We have selected liver diseases as our initial\plain\cf1\f51\fs20\i\ql in vivo\plain\cf1\f51\fs20\ql targets because delivery of nucleic acid therapies into the liver has\plain\cf1\f51\fs20\ql been clinically established and validated delivery technologies are now available, including, but not limited to, lipid\plain\cf1\f51\fs20\ql nanoparticle-based delivery vehicles, or LNPs, and adeno-associated viral vectors, or AAV vectors. We believe this proof of\plain\cf1\f51\fs20\ql concept reduces the challenges associated with delivering CRISPR/Cas9-based therapeutics\plain\cf1\f51\fs20\i\ql in vivo\plain\cf1\f51\fs20\ql to the liver.\par\pard\plain\sb264\cf1\f51\fs20\qc 11\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We have observed promising preclinical results in our studies with both viral and non-viral delivery technologies. For\plain\cf1\f51\fs20\ql example, using LNPs, we were able to demonstrate approximately 80% editing rates in mouse models at the target gene which\plain\cf1\f51\fs20\ql resulted in greater than 85% reduction in the expression of the gene as measured by protein levels in the serum, as shown in the\plain\cf1\f51\fs20\ql figure below.\par\pard\plain\cf1\f51\fs8\b\qc \~\par\pard\plain\cf1\f51\fs8\b\qc \~\par\pard\plain\cf1\f51\fs8\b\qc \~\par\pard\plain\cf1\f51\fs20\b\qc Significant decrease in serum C3 levels after editing\plain\cf1\f51\fs20\b\i\qc in vivo\plain\cf1\f51\fs18\b\qc\super 1\par\qc\sb264{\*\shppict{\pict\pngblip\picw610\pich288\picscalex74\picscaley74\bliptag-9728958103
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\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Within the liver we are pursuing diseases that have well understood genetic linkages and have begun preclinical\plain\cf1\f51\fs20\ql development for multiple indications including glycogen storage disease Ia, or GSDIa, and hemophilia. In both of these\plain\cf1\f51\fs20\ql indications, evidence suggests that correction of the mutant gene in only a small percentage of liver cells may have a significant\plain\cf1\f51\fs20\ql therapeutic effect, which makes the gene correction strategy feasible in these indications.\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql Glycogen Storage Disease Ia\par\pard\plain\li44\sb132\cf1\f51\fs20\i\ql Overview\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql GSDIa, also known as Von Gierke disease, is an autosomal recessive inborn error of glucose metabolism caused by a\plain\cf1\f51\fs20\ql mutation in the G6PC gene, which encodes the glucose-6-phosphatase protein, or G6Pase. In patients with GSDIa, the lack of\plain\cf1\f51\fs20\ql G6Pase prevents the release of glucose from the liver, resulting in accumulation of a large chain form of glucose known as\plain\cf1\f51\fs20\ql glycogen. The inability of patients with GSDIa to regulate glucose levels leads to hypoglycemia, or low blood glucose, and high\plain\cf1\f51\fs20\ql levels of lactic acid when patients are not eating, requiring patients to adhere to burdensome dietary regimes. GSDIa patients also\plain\cf1\f51\fs20\ql face long-term risks such as growth delay, neuropathy and kidney stones. Additionally, due to the accumulation of glycogen in\plain\cf1\f51\fs20\ql the liver, 70% to 80% of patients over 25\~years of age will develop hepatocellular adenomas, a type of non-cancerous growth in\plain\cf1\f51\fs20\ql the liver, of which approximately 10% will progress to hepatocellular carcinoma, a potentially fatal liver cancer. There are\plain\cf1\f51\fs20\ql approximately 1,000 new cases of GSDIa per year worldwide.\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Limitations of Current Treatment Options\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql There are currently no disease-modifying treatment options for patients with GSDIa. Any disruption in carbohydrate\plain\cf1\f51\fs20\ql delivery may lead to low blood sugar levels, which can cause life-threatening consequences including seizure, coma and death.\plain\cf1\f51\fs20\ql To minimize the risk of acute complications, patients are required to adhere to highly burdensome, lifelong dietary regimens such\plain\cf1\f51\fs20\ql as overnight administration of uncooked cornstarch or a slow-release carbohydrate product such as Glycosade. These regimens\plain\cf1\f51\fs20\ql have a high rate of non-compliance, leading to increased risk of serious long-term complications.\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Our Gene Editing Approach\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We are developing a CRISPR/Cas9 product candidate to correct the mutation in GSDIa patients. Animal model experiments\plain\cf1\f51\fs20\ql have demonstrated that the addition of functional copies of the G6PC gene is capable of correcting the deficiency of G6Pase\plain\cf1\f51\fs20\ql protein in GSDIa and that as little as 3% of normal levels of G6Pase can restore the equilibrium of glucose and glycogen in the\plain\cf1\f51\fs20\ql bloodstream and liver. Our approach is to correct the G6PC gene directly in its native location. We believe this direct gene\plain\cf1\f51\fs20\ql correction will result in appropriate expression of the G6Pase protein. Other methods rely on adding copies of the gene through\plain\cf1\f51\fs20\ql viral delivery methods, which we believe may lead to overexpression of the G6Pase protein and ineffective control of glucose\plain\cf1\f51\fs20\ql levels.\par\pard\plain\sb264\cf1\f51\fs20\qc 12\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql Hemophilia\par\pard\plain\li44\sb132\cf1\f51\fs20\i\ql Overview\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Hemophilia is an X-linked recessive genetic disease primarily present in male children. Our initial hemophilia program\plain\cf1\f51\fs20\ql targets hemophilia\~B, which results from a deficiency in factor IX, an enzyme produced in the liver. Factor IX is part of the\plain\cf1\f51\fs20\ql blood coagulation system, which enables blood to form clots in response to injury and bleeding. A\~lack of factor IX leads to an\plain\cf1\f51\fs20\ql increased risk of bleeding, either spontaneously or in response to injury.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Patients with severe forms of the disease are first diagnosed at infancy, as witnessed through prolonged bleeding from\plain\cf1\f51\fs20\ql simple medical procedures or through excessive bruising from simple falls. These patients have frequent spontaneous bleeding\plain\cf1\f51\fs20\ql into joints and muscles, which can lead to edema, inflammation and debilitating pain. Patients with mild forms of the disease\plain\cf1\f51\fs20\ql typically present as normal, and diagnosis usually follows surgery or trauma. The worldwide prevalence of hemophilia\~B patients\plain\cf1\f51\fs20\ql is estimated to be 28,000, including over 4,000 in the United States. About half of hemophilia B cases are classified as severe\plain\cf1\f51\fs20\ql based on levels of factor IX activity that are less than 1% of normal.\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Limitations of Current Treatment Options\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql The standard of care for symptomatic patients with hemophilia B involves enzyme replacement with recombinant factor IX.\plain\cf1\f51\fs20\ql Exogenous factor IX protein is administered both as a prophylaxis and during acute bleeding episodes. While considered\plain\cf1\f51\fs20\ql effective, factor IX replacement therapies are invasive, inconvenient and non-curative. Until recently, hemophilia B therapy\plain\cf1\f51\fs20\ql required weekly intravenous injections or infusions. While administration frequency has improved in recent years, key drawbacks\plain\cf1\f51\fs20\ql of protein therapy, including fluctuations in factor\~IX levels, remain a significant pitfall of enzyme replacement therapies.\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Our Gene Editing Approach\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We believe that hemophilia B symptoms can be dramatically reduced with only a moderate restoration in factor IX activity.\plain\cf1\f51\fs20\ql It has been shown that patients with more than 5% of normal factor IX activity have milder forms of the disease and may not\plain\cf1\f51\fs20\ql present symptoms in the absence of trauma or surgery. This observation implies that in patients with severe forms of the disease,\plain\cf1\f51\fs20\ql restoration of factor IX activity to a level of 5% or more of normal may be clinically meaningful.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The correction of a mutant factor IX gene with CRISPR/Cas9 leverages endogenous regulation via correction of the gene at\plain\cf1\f51\fs20\ql its native location within the genome. As a result, we believe it may represent a superior way to treat hemophilia B patients,\plain\cf1\f51\fs20\ql relative to other gene therapy approaches that insert the correct gene at a random location in the genome. Our hemophilia\plain\cf1\f51\fs20\ql program will be developed within the Casebia joint venture, leveraging Bayer\u8217?s expertise in this disease area together with\plain\cf1\f51\fs20\ql our gene editing expertise.\par\pard\plain\sb396\cf1\f51\fs20\b\ql Other Organs\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql In addition, we have initiated several\plain\cf1\f51\fs20\i\ql in vivo\plain\cf1\f51\fs20\ql programs targeting diseases of organ systems outside the liver, such as\plain\cf1\f51\fs20\ql Duchenne muscular dystrophy, or DMD, and cystic fibrosis, or CF. In CF, we are working with Vertex, a global leader with\plain\cf1\f51\fs20\ql extensive disease area expertise. We believe that our CRISPR/Cas9 gene editing technology is well suited to address these\plain\cf1\f51\fs20\ql diseases, both of which have significant patient populations with high unmet medical need.\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql Duchenne Muscular Dystrophy\par\pard\plain\li44\sb132\cf1\f51\fs20\i\ql Overview\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Duchenne muscular dystrophy is an X-linked recessive genetic disease caused by a mutation in the dystrophin gene, which\plain\cf1\f51\fs20\ql results in a lack of the dystrophin protein, a protein that plays a key structural role in muscle fiber function. The absence of\plain\cf1\f51\fs20\ql dystrophin in muscle cells leads to significant cell damage and ultimately causes muscle cell death and fibrosis. DMD is\plain\cf1\f51\fs20\ql characterized by muscle degeneration, loss of mobility and premature death, and is among the most prevalent severe genetic\plain\cf1\f51\fs20\ql diseases, occurring in one in 3,300 male births worldwide. There is also a related form of muscular dystrophy called Becker\plain\cf1\f51\fs20\ql muscular dystrophy, or BMD, which is also caused by mutations in the dystrophin gene. However, unlike DMD, the mutations in\plain\cf1\f51\fs20\ql BMD result in the loss of certain exons or regions of the gene and can lead to an abnormal version of dystrophin that retains\plain\cf1\f51\fs20\ql some function. As a result, BMD patients have milder symptoms than DMD patients.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql There is currently one approved disease-modifying therapy in the United States for the treatment of DMD in patients who\plain\cf1\f51\fs20\ql have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13% of the population with\plain\cf1\f51\fs20\ql DMD. This therapy involves the use of oligonucleotides to promote exon skipping over the mutations that otherwise would result\plain\cf1\f51\fs20\ql in truncated dystrophin synthesis. While exon skipping has demonstrated promising results in limited settings, larger clinical trials\plain\cf1\f51\fs20\ql of this approach have suggested only modest efficacy. In addition, delivering sufficient levels of oligonucleotides requires\plain\cf1\f51\fs20\ql repeated administration and presents challenges to treating DMD.\par\pard\plain\sb264\cf1\f51\fs20\qc 13\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Our Gene Editing Approach\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We are pursuing multiple approaches to developing therapies for DMD. Our first approach is to deliver CRISPR/Cas9\plain\cf1\f51\fs20\ql directly to muscle cells in patients to delete the defective exons in the dystrophin gene. The goal of this approach is to allow the\plain\cf1\f51\fs20\ql gene to regain some functional capacity and produce enough dystrophin protein to diminish the more severe symptoms of DMD\plain\cf1\f51\fs20\ql to resemble the milder form of the disease known as BMD. We believe that currently available technology is capable of\plain\cf1\f51\fs20\ql delivering the CRISPR/Cas9 into muscle cells, and together with the relatively high efficiency of exon deletion using the\plain\cf1\f51\fs20\ql CRISPR/Cas9 system, we will be able to move this program into clinical testing.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In parallel, we are performing\plain\cf1\f51\fs20\i\ql in vitro\plain\cf1\f51\fs20\ql experiments to test the principle of dystrophin gene correction which could\plain\cf1\f51\fs20\ql potentially be curative. Prior studies in mice and humans have indicated that dystrophin levels as low as 4 to 15% of normal are\plain\cf1\f51\fs20\ql sufficient to ameliorate symptoms, suggesting that even a partial restoration of dystrophin levels would be therapeutically\plain\cf1\f51\fs20\ql beneficial.\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql Cystic Fibrosis\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Cystic fibrosis is a progressive disease caused by mutations in the cystic fibrosis transmembrane regulator, or CFTR, gene\plain\cf1\f51\fs20\ql resulting in the loss or reduced function of the CFTR protein. Although there are several different mutations associated with CF,\plain\cf1\f51\fs20\ql approximately 70% of CF patients have the same mutation at codon 508 of the CFTR gene. Patients with CF develop thick\plain\cf1\f51\fs20\ql mucus in vital organs, particularly in the lungs, pancreas and gastrointestinal tract. As a result, CF patients experience chronic\plain\cf1\f51\fs20\ql severe respiratory infections, chronic lung inflammation, poor absorption of nutrients, progressive respiratory failure and early\plain\cf1\f51\fs20\ql mortality.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql CF is an orphan disease that affects an estimated 70,000 to 100,000 patients worldwide, with a majority in the United\plain\cf1\f51\fs20\ql States and Europe. The median age of death from CF in the United States in 2015 was 29 years, with most deaths resulting from\plain\cf1\f51\fs20\ql respiratory failure. CF patients require lifelong treatment with multiple daily medications and hours of self-care. They often\plain\cf1\f51\fs20\ql require frequent hospitalizations and sometimes even lung transplantation, which can prolong survival but is not curative.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Studies have shown that as little as 10% of normal CFTR function can ameliorate disease symptoms. Our approach is\plain\cf1\f51\fs20\ql focused on using our CRISPR/Cas9 technology to correct mutations in the CFTR gene. Together with our collaboration partner\plain\cf1\f51\fs20\ql Vertex, we believe that we will be able to deliver CRISPR/Cas9 to the lung and correct this mutation sufficiently to improve\plain\cf1\f51\fs20\ql symptoms in patients with CF.\par\pard\plain\sb396\cf1\f51\fs20\b\ql Further Unlocking the Potential of Our CRISPR/Cas9 Platform\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We are working to optimize our CRISPR/Cas9 platform. Our key areas of focus are described below.\par\pard\plain\cf1\f51\fs24\ql \~\par\qc{\*\shppict{\pict\pngblip\picw574\pich358\picscalex74\picscaley74\bliptag-9728958103
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\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb264\cf1\f51\fs20\qc 14\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\li44\sb176\cf1\f51\fs20\b\i\ql Nuclease Engineering\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql The Cas9 nucleases found in nature are highly efficient and specific. We believe that for many gene-editing applications,\plain\cf1\f51\fs20\ql the naturally occurring Cas9 variants have all the properties required to support an effective therapeutic. However, we also see\plain\cf1\f51\fs20\ql potential in certain disease areas and organ systems where modified versions of Cas9 may be more effective, and we are working\plain\cf1\f51\fs20\ql internally and through our external collaborations to develop these.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Our research and development efforts seek to enhance a number of characteristics of Cas9, including size, specificity,\plain\cf1\f51\fs20\ql immunogenicity and ability to support different types of editing strategies. We believe that the process of optimizing these\plain\cf1\f51\fs20\ql different parameters may yield a number of effective Cas9 versions with different properties, each of which may be best suited to\plain\cf1\f51\fs20\ql a certain disease area or type of genetic editing.\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql Guide RNA Optimization\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Selecting the sequence for guide RNAs is a critical step in the process of designing our product candidates. Once we have\plain\cf1\f51\fs20\ql chosen a gene editing strategy, we seek to identify guide RNAs that will perform the desired edit with high efficiency and with\plain\cf1\f51\fs20\ql extremely low off-target cutting. While computational models can predict efficiency and off-target effects with reasonable\plain\cf1\f51\fs20\ql accuracy, we believe that a combination of computation and experimental approaches is necessary to reliably select the best\plain\cf1\f51\fs20\ql possible guide RNAs.\par\pard\plain\sb44\cf1\f51\fs20\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql Our guide RNA selection process combines bioinformatics and experimental assays to enable the screening of large\plain\cf1\f51\fs20\ql numbers of guide RNAs in each experiment. This process starts with proprietary bioinformatics algorithms that select a large pool\plain\cf1\f51\fs20\ql of guide RNAs that are predicted to have desired properties. These guides are then tested for target site cutting efficiency using a\plain\cf1\f51\fs20\ql high-throughput screening platform in a model cell line. The most efficient guides are then put through two screening processes\plain\cf1\f51\fs20\ql for possible off-target effects. First, bioinformatics algorithms are used to identify the 10 to 20 sites in the genome that are most\plain\cf1\f51\fs20\ql likely to show off-target effects, and these sites are examined through high-throughput assays for empirical off-target cutting.\plain\cf1\f51\fs20\ql Second, homology-independent screening is performed to identify any potential off-target cutting, even at unpredicted locations.\plain\cf1\f51\fs20\ql Finally, a small subset of guides with the highest efficiency and lowest off-target potential are tested in the cell type of\plain\cf1\f51\fs20\ql therapeutic interest before choosing a lead guide or guides for our program.\par\pard\plain\sb396\fi264\cf1\f51\fs20\b\i\ql Advanced Editing\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql While gene correction is achievable today using CRISPR/Cas9, it is more difficult and has lower efficacy than the more\plain\cf1\f51\fs20\ql straightforward gene disruption strategy. Our initial gene correction programs target diseases in which therapeutic efficacy can be\plain\cf1\f51\fs20\ql achieved through correction of only a small percentage of cells, while other potential indications may require correction of a\plain\cf1\f51\fs20\ql significantly higher percentage of cells. We are working with our collaborators to increase the efficiency of gene correction in\plain\cf1\f51\fs20\ql order to facilitate the potential treatment of these additional indications.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql A central focus of our development efforts is to optimize the correction rates in cell types where rates of correction are\plain\cf1\f51\fs20\ql typically low. Some of this optimization is being done internally, to test the influence of different parameters of the\plain\cf1\f51\fs20\ql CRISPR/Cas9 system on correction efficiency. In addition, we are advised by Dr. Stephen Elledge, Professor of Genetics at\plain\cf1\f51\fs20\ql Harvard Medical School, who is an expert in DNA damage and repair, to explore ways to optimize the cellular processes\plain\cf1\f51\fs20\ql involved in the correction process. We are also collaborating more broadly with leaders in the DNA repair field, to explore other\plain\cf1\f51\fs20\ql approaches to optimize correction rates.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We are also focused on expanding our ability to perform multiple edits simultaneously. In contrast to other gene editing\plain\cf1\f51\fs20\ql technologies, which require extensive protein engineering and an additional construct for each new genetic target, CRISPR/Cas9\plain\cf1\f51\fs20\ql only requires a new guide RNA using simple Watson-Crick base pairing to target a new genetic locus. As a result, one can\plain\cf1\f51\fs20\ql easily perform many edits at once using CRISPR/Cas9, a process known as multiplexing. Multiplexing holds particular promise\plain\cf1\f51\fs20\ql in cellular therapies, where making several modifications may lead to a safer and more efficacious therapy. Our research efforts\plain\cf1\f51\fs20\ql in this area emphasize developing strategies to keep editing rates high while multiplexing without increasing the risk of off-target\plain\cf1\f51\fs20\ql activity.\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql Stem Cell Engineering\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Many\plain\cf1\f51\fs20\i\ql ex vivo\plain\cf1\f51\fs20\ql applications of our technology use a strategy of editing stem cells\plain\cf1\f51\fs20\i\ql ex vivo\plain\cf1\f51\fs20\ql which, when returned to the\plain\cf1\f51\fs20\ql patient, differentiate into a variety of different cell types. For certain stem cell types, especially hematopoietic cells, there are\plain\cf1\f51\fs20\ql well-established procedures to support this strategy. For others, these procedures are more nascent and require further\plain\cf1\f51\fs20\ql development. A critical focus for us is to improve the efficacy, efficiency and safety of the\plain\cf1\f51\fs20\i\ql ex vivo\plain\cf1\f51\fs20\ql cell collection, manipulation\plain\cf1\f51\fs20\ql and administration process for a variety of stem cell types. We are evaluating technologies to improve mobilization of a\plain\cf1\f51\fs20\ql patient\u8217?s stem cells, to maintain viability of the harvested cells and to improve the ability of these cells to engraft into a\plain\cf1\f51\fs20\ql patient\u8217?s body. Both in our own laboratories and through our academic partnerships, we intend to perform additional\plain\cf1\f51\fs20\ql research to optimize these parameters for each organ system.\par\pard\plain\sb264\cf1\f51\fs20\qc 15\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb396\cf1\f51\fs20\b\ql Strategic Partnerships and Collaborations\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We intend to develop CRISPR/Cas9-based therapeutics both independently and in collaboration with current and potential\plain\cf1\f51\fs20\ql future corporate partners. We view strategic partnerships as a core component of our strategy, allowing us to access capabilities\plain\cf1\f51\fs20\ql and resources in support of our therapeutic programs. We have established two broad strategic partnerships \u8211? a research\plain\cf1\f51\fs20\ql collaboration with Vertex Pharmaceuticals Incorporated and a joint venture with Bayer HealthCare \u8211? to develop\plain\cf1\f51\fs20\ql gene-editing-based therapeutics in specific disease areas. Our partnerships with Bayer and Vertex provide over $400 million,\plain\cf1\f51\fs20\ql inclusive of estimated spending on funded programs, which will be used to advance the programs included in these partnerships.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Under our agreement with Bayer HealthCare, we established Casebia Therapeutics LLP, or Casebia, a joint venture in\plain\cf1\f51\fs20\ql which we and Bayer HealthCare are equal owners. We and Bayer intend for Casebia to largely focus on more challenging\plain\cf1\f51\fs20\i\ql in vivo\plain\cf1\f51\fs20\ql therapeutic areas in larger patient populations, and to invest resources in optimizing the platform and delivery technologies for\plain\cf1\f51\fs20\i\ql in\plain\cf1\f51\fs20\i\ql vivo\plain\cf1\f51\fs20\ql delivery. Through our agreement, we will have access to technology enhancements developed or obtained by Casebia for the\plain\cf1\f51\fs20\ql benefit of our other wholly owned programs.{\*\bkmkstart _hlk507411287_12116663}{\*\bkmkend _hlk507411287_12116663}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Our agreement with Vertex is a two-part collaboration. We granted Vertex an option to co-develop and co-commercialize\plain\cf1\f51\fs20\ql rights to the hemoglobinopathies program and\~options to license certain other programs with the potential to receive milestone\plain\cf1\f51\fs20\ql payments and royalties. Since signing the original agreement, Vertex has exercised their option to co-develop and\plain\cf1\f51\fs20\ql co-commercialize the hemoglobinopathies program for which net profits and losses, as applicable, will be shared equally by the\plain\cf1\f51\fs20\ql parties.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Enabling Technologies\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql In support of our lead\plain\cf1\f51\fs20\i\ql ex vivo\plain\cf1\f51\fs20\ql programs, we have entered into a commercial license agreement with MaxCyte Incorporated.\plain\cf1\f51\fs20\ql The license provides CRISPR and Casebia a non-exclusive commercial-use right to MaxCyte\u8217?s cell engineering platform\plain\cf1\f51\fs20\ql to develop CRISPR/Cas9-based therapies for hemoglobin-related diseases and severe combined immunodeficiency. Our lead\plain\cf1\f51\fs20\ql program, CTX001, utilizes MaxCyte\u8217?s Flow Electroporation\u8482? Technology to deliver CRISPR/Cas9 components to\plain\cf1\f51\fs20\ql hematopoietic stem cells.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We have also formed several collaborations to support our\plain\cf1\f51\fs20\i\ql in vivo\plain\cf1\f51\fs20\ql programs. Together with Casebia, we have a\plain\cf1\f51\fs20\ql collaboration with CureVac AG to develop novel Cas9 mRNA constructs with improved properties for gene editing in the liver,\plain\cf1\f51\fs20\ql such as increased potency, decreased duration of expression and reduced potential for immunogenicity. As part of the\plain\cf1\f51\fs20\ql collaboration, CureVac will provide mRNA manufacturing through clinical development and commercialization.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We have also entered into a development and option agreement with StrideBio LLC to develop novel AAV vectors for\plain\cf1\f51\fs20\i\ql in\plain\cf1\f51\fs20\i\ql vivo\plain\cf1\f51\fs20\ql gene editing applications. Under the agreement, StrideBio will use its proprietary structure-guided evolution platform to\plain\cf1\f51\fs20\ql develop AAV vectors with improved properties, such as tissue specificity and reduced susceptibility to immune responses. Under\plain\cf1\f51\fs20\ql this agreement we have the option to exclusively license AAV vectors with desired properties for certain of our\plain\cf1\f51\fs20\i\ql in vivo\plain\cf1\f51\fs20\ql programs.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Additionally, we have access to non-viral delivery technology through an exclusive license from the Massachusetts Institute\plain\cf1\f51\fs20\ql of Technology to a family of LNP technologies developed in the lab of Dr. Daniel G. Anderson, a scientific founder and\plain\cf1\f51\fs20\ql advisory board member of CRISPR Therapeutics.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Academic and Discovery Collaborations\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We have a two-year research collaboration and license option agreement with Massachusetts General Hospital Cancer\plain\cf1\f51\fs20\ql Center, or MGHCC, to develop novel T cell therapies for cancer. Marcela V. Maus, MD, PhD, Director of the Cellular\plain\cf1\f51\fs20\ql Immunotherapy Program at MGHCC and Assistant Professor of Medicine at Harvard Medical School, will lead the scientific\plain\cf1\f51\fs20\ql work at MGHCC. The research will involve using CRISPR/Cas9 gene editing to improve upon current T cell therapies in\plain\cf1\f51\fs20\ql development, ultimately addressing unmet needs in both hematologic and solid tumors.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Also in the immuno-oncology space, we have a research collaboration with Neon Therapeutics, an immuno-oncology\plain\cf1\f51\fs20\ql company developing neoantigen-based therapeutic vaccines and T cell therapies to treat cancer. The collaboration combines our\plain\cf1\f51\fs20\ql respective proprietary technologies to explore the development of novel T cell therapies.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We and our collaborators at the University of Florida, or UF, have received a two-year grant from Target ALS Foundation\plain\cf1\f51\fs20\ql to support preclinical discovery and validation of CRISPR/Cas9-based therapeutic approaches directed to ALS and\plain\cf1\f51\fs20\ql frontotemporal dementia. We will collaborate with Dr. Laura Ranum and Dr. Eric Wang at UF to test CRISPR/Cas9 gene editing\plain\cf1\f51\fs20\ql strategies in animal models of the disease.\par\pard\plain\sb264\cf1\f51\fs20\qc 16\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We also received the Kyle Bryant Translational Research Award from Friedreich\u8217?s Ataxia Research Alliance, or\plain\cf1\f51\fs20\ql FARA, a non-profit organization that is focused on curing Friedreich\u8217?s Ataxia, or FA. The grant will fund research on\plain\cf1\f51\fs20\i\ql in\plain\cf1\f51\fs20\i\ql vivo\plain\cf1\f51\fs20\ql CRISPR/Cas9-based gene-editing approaches to treat FA, which we will conduct in collaboration with Dr. Marek Napierala\plain\cf1\f51\fs20\ql at University of Alabama at Birmingham.\par\pard\plain\sb396\cf1\f51\fs20\b\ql Intellectual Property\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We strive to protect and enhance the proprietary technologies that we believe are important to our business by seeking\plain\cf1\f51\fs20\ql patents to cover our platform technology, which consists of the in-licensed intellectual property of Dr. Emmanuelle Charpentier\plain\cf1\f51\fs20\ql described below, including compositions of matter and their therapeutic uses. We also rely on trade secrets to protect aspects of\plain\cf1\f51\fs20\ql our business that are not amenable to, or that we do not consider appropriate for, patent protection. Our success will depend\plain\cf1\f51\fs20\ql significantly on our ability to obtain and maintain patent and other proprietary protection for our technology, our ability to defend\plain\cf1\f51\fs20\ql and enforce our intellectual property rights and our ability to operate without infringing any valid and enforceable patents and\plain\cf1\f51\fs20\ql proprietary rights of third parties.\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql In-Licensed Intellectual Property\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql In April 2014, pursuant to an exclusive license with Dr.\~Emmanuelle Charpentier, we licensed from Dr. Charpentier certain\plain\cf1\f51\fs20\ql rights to a family of patent applications relating to compositions of matter, including additional CRISPR/TRACR/Cas9\plain\cf1\f51\fs20\ql complexes, and methods of use, including their use in targeting or cutting DNA. This license is limited to therapeutic products\plain\cf1\f51\fs20\ql such as pharmaceuticals and biologics and any associated companion diagnostics, for the treatment or prevention of human\plain\cf1\f51\fs20\ql diseases, disorders, or conditions. For further information about this license, please see \u8220?Business \u8211? CRISPR License\plain\cf1\f51\fs20\ql with Dr.\~Emmanuelle Charpentier.\u8221?\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql This family of patent applications includes approximately eight (8) granted or allowed patents in the United Kingdom,\plain\cf1\f51\fs20\ql Europe, China, New Zealand, Singapore, Australia and Mexico, and pending patent applications in the United States, Europe,\plain\cf1\f51\fs20\ql Canada, Mexico, Australia and other selected countries in Central America, South America, Asia and Africa. The granted patents\plain\cf1\f51\fs20\ql and any other patents that may ultimately issue in this patent family are expected to expire in 2033, not including any applicable\plain\cf1\f51\fs20\ql extensions.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In addition to Dr.\~Emmanuelle Charpentier, this family of patent applications has named inventors who assigned their rights\plain\cf1\f51\fs20\ql either to the Regents of the University of California, or California, or the University of Vienna, or Vienna. California\u8217?s\plain\cf1\f51\fs20\ql rights are subject to certain overriding obligations to the sponsors of its research, including the Howard Hughes Medical Institute\plain\cf1\f51\fs20\ql and the U.S. Government. Caribou Biosciences, or Caribou, had reported that it had an exclusive license to patent rights from\plain\cf1\f51\fs20\ql California and Vienna, subject to a retained right to allow non-profit entities to use the inventions for research and educational\plain\cf1\f51\fs20\ql purposes. Intellia Therapeutics, Inc., or Intellia, had reported that it had an exclusive license to such rights from Caribou in\plain\cf1\f51\fs20\ql certain fields.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In January 2016, the U.S. Patent and Trademark Office, or USPTO, declared an interference between one of the pending\plain\cf1\f51\fs20\ql U.S. patent applications in this family and twelve issued U.S. patents owned jointly by the Broad Institute and Massachusetts\plain\cf1\f51\fs20\ql Institute of Technology and, in some instances, the President and Fellows of Harvard College, which we refer to individually and\plain\cf1\f51\fs20\ql collectively as Broad. The interference was redeclared in March 2016 to add a U.S. patent application owned by Broad. An\plain\cf1\f51\fs20\ql interference is a proceeding conducted at the USPTO by the Patent Trial and Appeal Board, or PTAB, to determine which party\plain\cf1\f51\fs20\ql was the first to invent subject matter claimed by at least two parties. There are currently two parties to this interference. The\plain\cf1\f51\fs20\ql USPTO designated Dr.\~Emmanuelle Charpentier, California and Vienna collectively as \u8220?Senior Party\u8221? and\plain\cf1\f51\fs20\ql designated Broad as \u8220?Junior Party.\u8221? Following motions by the parties and other procedural matters, the PTAB\plain\cf1\f51\fs20\ql concluded in February 2017 that the declared interference should be dismissed because the claim sets of the two parties were not\plain\cf1\f51\fs20\ql directed to the same patentable invention in accordance with the PTAB\u8217?s two-way test for patent interferences. In\plain\cf1\f51\fs20\ql particular, the Junior Party\u8217?s claims in the interference were all limited to uses in eukaryotic cells, while the Senior\plain\cf1\f51\fs20\ql Party\u8217?s claims in the interference were not limited to uses in eukaryotic cells but included uses in all settings. Senior Party\plain\cf1\f51\fs20\ql has appealed the decision to the U.S. Court of Appeals for the Federal Circuit. In parallel, either party can also pursue existing or\plain\cf1\f51\fs20\ql new patent applications in the U.S. and elsewhere. Going forward, either party as well as other parties could seek a new\plain\cf1\f51\fs20\ql interference related to the uses of the technology in eukaryotic cells or other aspects of the technology, and any existing or new\plain\cf1\f51\fs20\ql patents could be the subject of other challenges to their validity of enforceability. If there is a second interference, either party\plain\cf1\f51\fs20\ql could again appeal an adverse decision to the U.S. Court of Appeals for the Federal Circuit. In any case, it may be years before\plain\cf1\f51\fs20\ql there is a final determination on priority. Pursuant to the terms of the license agreement with Dr. Charpentier, we are responsible\plain\cf1\f51\fs20\ql for covering or reimbursing Dr. Charpentier\u8217?s patent prosecution, defense and related costs associated with our in-licensed\plain\cf1\f51\fs20\ql technology. For further information regarding risks regarding the interference and patent rights held by third parties, please see\plain\cf1\f51\fs20\ql \u8220?Risk Factors\u8212?Risks Related to Our Intellectual Property.\u8221?\par\pard\plain\sb264\cf1\f51\fs20\qc 17\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql On December\~15, 2016, we entered into a Consent to Assignments, Licensing and Common Ownership and Invention\plain\cf1\f51\fs20\ql Management Agreement, or the IMA, with California, Vienna, Dr. Charpentier, Intellia, Caribou, ERS Genomics Ltd., or ERS,\plain\cf1\f51\fs20\ql and TRACR. Under the IMA, California and Vienna retroactively consent to Dr.\~Charpentier\u8217?s licensing of her rights to\plain\cf1\f51\fs20\ql the CRISPR/Cas9 intellectual property, pursuant to our license with Dr. Charpentier, to us, our wholly-owned subsidiary\plain\cf1\f51\fs20\ql TRACR, and ERS, in the United States and globally. The IMA also provides retroactive consent of co-owners to sublicenses\plain\cf1\f51\fs20\ql granted by us, TRACR and other licensees, prospective consent to sublicenses they may grant in future, retroactive approval of\plain\cf1\f51\fs20\ql prior assignments by certain parties, and provides for, among other things, (i)\~good faith cooperation among the parties regarding\plain\cf1\f51\fs20\ql patent maintenance, defense and prosecution, (ii)\~cost-sharing arrangements, and (iii)\~notice of and coordination in the event of\plain\cf1\f51\fs20\ql third-party infringement of the subject patents and with respect to certain adverse claimants of the CRISPR/Cas9 intellectual\plain\cf1\f51\fs20\ql property. Unless earlier terminated by the parties, the IMA will continue in effect until the later of the last expiration date of the\plain\cf1\f51\fs20\ql patents underlying the CRISPR/Cas9 technology, or the date on which the last underlying patent application is abandoned. For\plain\cf1\f51\fs20\ql further information regarding the effects of joint ownership in the United States and in other jurisdictions worldwide, please see\plain\cf1\f51\fs20\ql \u8220?Risk Factors \u8211?\plain\cf1\f51\fs20\i\ql The Intellectual Property That Protects Our Core Gene Editing Technology Is Jointly Owned, And\plain\cf1\f51\fs20\i\ql Our License Is From Only One Of The Joint Owners, Materially Limiting Our Rights In The United States And In Other\plain\cf1\f51\fs20\i\ql Jurisdictions\plain\cf1\f51\fs20\ql .\u8221?\~\~\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql CRISPR-Owned Intellectual Property\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We also own over 40\~families of patent applications relating to our platform technology or its therapeutic applications.\plain\cf1\f51\fs20\ql These patent applications are currently pending in the United States and in some cases in other countries, and we may elect to\plain\cf1\f51\fs20\ql pursue additional related applications internationally. Any patents that ultimately issue from these patent applications may begin\plain\cf1\f51\fs20\ql to expire in 2034.\par\pard\plain\sb396\cf1\f51\fs20\b\ql Patent Assignment Agreement\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql In November 2014, we entered into a patent assignment agreement with Dr.\~Emmanuelle Charpentier, Dr.\~Ines Fonfara and\plain\cf1\f51\fs20\ql Vienna, or the Patent Assignment Agreement. Under the Patent Assignment Agreement, Dr.\~Charpentier, Dr.\~Fonfara and Vienna\plain\cf1\f51\fs20\ql assigned to us all rights to a family of patent applications relating to certain compositions of matter, including additional\plain\cf1\f51\fs20\ql CRISPR/TRACR/Cas9 complexes, and methods of use, including their use in targeting or cutting DNA.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql As consideration for the patent rights assigned to us, we agreed to pay an upfront payment, milestone payments beginning\plain\cf1\f51\fs20\ql with the filing of a U.S. Investigational New Drug application or its equivalent in another country, a minimum annual royalty, a\plain\cf1\f51\fs20\ql low single-digit royalty on net sales of products whose manufacture, use, sale, or importation is covered by the assigned patent\plain\cf1\f51\fs20\ql rights, and a low single-digit percentage of licensing revenues.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We are obliged to use commercially reasonable efforts to obtain regulatory approval to market a product whose\plain\cf1\f51\fs20\ql manufacture, use, sale, or importation is covered by the assigned patent rights, including but not limited to an obligation to use\plain\cf1\f51\fs20\ql commercially reasonable efforts to file a U.S. Investigational New Drug application (or its equivalent in a major market country)\plain\cf1\f51\fs20\ql by November 2021.\par\pard\plain\sb396\cf1\f51\fs20\b\ql License Agreements\par\pard\plain\li44\sb132\cf1\f51\fs20\b\i\ql CRISPR License With Dr.\~Emmanuelle Charpentier\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql In April 2014, we entered into a license agreement, or the Charpentier License Agreement, with Dr.\~Emmanuelle\plain\cf1\f51\fs20\ql Charpentier, one of our co-founders, pursuant to which we received an exclusive license under Dr.\~Charpentier\u8217?s joint\plain\cf1\f51\fs20\ql ownership interest a family of patent applications relating to CRISPR/TRACR/Cas9 complexes and their use in targeting or\plain\cf1\f51\fs20\ql cutting DNA, which we refer to as the Patent Rights, to research, develop and commercialize therapeutic products such as\plain\cf1\f51\fs20\ql pharmaceuticals or biological preparations, and any associated companion diagnostics, for the treatment or prevention of human\plain\cf1\f51\fs20\ql diseases, disorders, or conditions, other than hemoglobinopathies, which we refer to as the CRISPR Field. The license is\plain\cf1\f51\fs20\ql exclusive, even as to Dr.\~Charpentier, except that she retains a non-transferable right to use the technology for her own research\plain\cf1\f51\fs20\ql purposes and in research collaborations with academic and non-profit partners. The exclusive license is granted only under Dr.\plain\cf1\f51\fs20\ql Charpentier\u8217?s interest in the patent applications and the exclusivity is not granted under any other joint owner\u8217?s\plain\cf1\f51\fs20\ql interest. Additionally, the Charpentier License Agreement granted us an exclusive, worldwide, royalty-free sublicense, including\plain\cf1\f51\fs20\ql the right to sublicense, to research, develop, produce, commercialize and sell therapeutic products relating to the CRISPR Field\plain\cf1\f51\fs20\ql which incorporate any intellectual property that TRACR Hematology Ltd., our wholly-owned subsidiary, or TRACR, develops\plain\cf1\f51\fs20\ql under its license with Dr.\~Charpentier. In turn, we granted to Dr.\~Charpentier an exclusive license with the obligation to\plain\cf1\f51\fs20\ql sublicense to TRACR any intellectual property we develop under the license with Dr.\~Charpentier for treatment and prevention of\plain\cf1\f51\fs20\ql hemoglobinopathies in humans, including, without limitation, sickle cell disease and thalassemia.\par\pard\plain\sb264\cf1\f51\fs20\qc 18\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Under the terms of the Charpentier License Agreement, as consideration for the license, Dr. Charpentier received a\plain\cf1\f51\fs20\ql technology transfer fee, an immaterial annual maintenance fee, immaterial milestone payments that will be due after the initiation\plain\cf1\f51\fs20\ql of clinical trials, a low single digit percentage royalty on net sales of licensed products, and a low single digit percentage\plain\cf1\f51\fs20\ql royalties of sublicensing revenue. We are obligated to use commercially reasonable efforts to obtain regulatory approval to\plain\cf1\f51\fs20\ql market a licensed therapeutic product. CRISPR must use commercially reasonable efforts to file a U.S. Investigational New Drug\plain\cf1\f51\fs20\ql application (or its equivalent in a major market country for a therapeutic product in the CRISPR field) by April 2021. In addition,\plain\cf1\f51\fs20\ql CRISPR must file a U.S. Investigational New Drug application (or its equivalent in a major market country) for a therapeutic\plain\cf1\f51\fs20\ql product in the CRISPR field by April 2024.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Unless terminated earlier, the term of the Charpentier License Agreement will expire on a country-by-country basis, upon\plain\cf1\f51\fs20\ql the expiration of the last to expire valid claim of the Patent Rights in such country. We have the right to terminate the agreement\plain\cf1\f51\fs20\ql at will upon 60 days\u8217? written notice to Dr.\~Charpentier. We and Dr.\~Charpentier may terminate the agreement upon 90\plain\cf1\f51\fs20\ql days\u8217? notice in the event of a material breach by the other party, which is not cured during the 90-day notice period.\plain\cf1\f51\fs20\ql Dr.\~Charpentier may terminate the license agreement immediately if we challenge the enforceability, validity, or scope of any\plain\cf1\f51\fs20\ql Patent Rights.\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql TRACR License With Dr.\~Emmanuelle Charpentier\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql In April 2014, concurrently with our license agreement with Dr.\~Emmanuelle Charpentier, TRACR Hematology Ltd., our\plain\cf1\f51\fs20\ql wholly- owned subsidiary, entered into a license agreement, or the TRACR License Agreement, with Dr.\~Charpentier, a minority\plain\cf1\f51\fs20\ql shareholder of TRACR, under the Patent Rights. Pursuant to the TRACR License Agreement, TRACR was granted an exclusive,\plain\cf1\f51\fs20\ql worldwide, royalty-bearing license, including the right to sublicense, to research, develop, produce, commercialize and sell\plain\cf1\f51\fs20\ql therapeutic and diagnostic products for the treatment and prevention of hemoglobinopathies in humans, including sickle cell\plain\cf1\f51\fs20\ql disease and thalassemia, or the TRACR Field. TRACR also received a non-exclusive, worldwide, royalty-free license, including\plain\cf1\f51\fs20\ql the right to sublicense, to carry out internal pharmaceutical research for therapeutic products outside of the TRACR Field and an\plain\cf1\f51\fs20\ql exclusive, worldwide, royalty-free sublicense, including the right to sublicense, to research, develop, produce, commercialize and\plain\cf1\f51\fs20\ql sell therapeutic products relating to the TRACR Field which incorporate any intellectual property that CRISPR develops under its\plain\cf1\f51\fs20\ql license with Dr.\~Charpentier. In turn, TRACR granted to Dr.\~Charpentier an exclusive license to sublicense to CRISPR any\plain\cf1\f51\fs20\ql intellectual property that TRACR develops under the license with Dr.\~Charpentier for use in the CRISPR Field.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql TRACR is obligated to use commercially reasonable efforts to research, develop, and commercialize at least one therapeutic\plain\cf1\f51\fs20\ql product for the prevention or treatment of human disease under the license agreement. TRACR must use commercially reasonable\plain\cf1\f51\fs20\ql efforts to file a U.S. Investigational New Drug application (or its equivalent in a major market country) for a therapeutic product\plain\cf1\f51\fs20\ql in the TRACR field by April 2021. In addition, TRACR must file a U.S. Investigational New Drug application (or its equivalent\plain\cf1\f51\fs20\ql in a major market country) for a therapeutic product in the TRACR field by April 2024. TRACR is solely responsible for all\plain\cf1\f51\fs20\ql clinical, regulatory and development costs.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Under the TRACR License Agreement, Dr.\~Emmanuelle Charpentier is entitled to receive immaterial clinical and regulatory\plain\cf1\f51\fs20\ql milestone payments per product that TRACR commercializes. TRACR is also required to pay Dr.\~Charpentier low single digit\plain\cf1\f51\fs20\ql percentage royalties on the net sales of any approved therapeutic or diagnostic products, made by it, its affiliates, or its\plain\cf1\f51\fs20\ql sublicensees and low single-digit percentage royalties on sublicensing revenue.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Unless terminated earlier, the term of the license agreement will expire on a country-by-country basis, upon the expiration\plain\cf1\f51\fs20\ql of the last to expire valid claim of the Patent Rights in such country. TRACR has the right to terminate the agreement at will\plain\cf1\f51\fs20\ql upon 60 days\u8217? written notice to Dr.\~Emmanuelle Charpentier. TRACR and Dr.\~Charpentier may terminate the agreement\plain\cf1\f51\fs20\ql upon 90 days\u8217? notice in the event of a material breach by the other party, which is not cured during the 90-day notice\plain\cf1\f51\fs20\ql period. Dr.\~Charpentier may terminate the license agreement immediately if TRACR challenges the enforceability, validity, or\plain\cf1\f51\fs20\ql scope of any Patent Right.\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql Bayer Joint Venture\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql In December 2015, we entered into a Joint Venture Agreement, or the JV Agreement, with Bayer HealthCare LLC, or\plain\cf1\f51\fs20\ql Bayer HealthCare, to create Casebia Therapeutics LLP, or Casebia, to discover, develop and commercialize new therapeutics for\plain\cf1\f51\fs20\ql genetically linked diseases, including blood disorders, blindness and heart disease. At the closing of the transactions contemplated\plain\cf1\f51\fs20\ql by the JV Agreement in March 2016, or the Closing, we contributed $0.1\~million to Casebia and we and certain of our affiliates\plain\cf1\f51\fs20\ql entered into an intellectual property contribution agreement with Casebia, or the CRISPR IP Contribution Agreement, as\plain\cf1\f51\fs20\ql discussed below, exclusively licensing our CRISPR/Cas technology to Casebia for the purpose of developing and commercializing\plain\cf1\f51\fs20\ql therapeutic products in certain specified fields, or the Casebia Fields. Bayer HealthCare contributed an initial amount of $45\plain\cf1\f51\fs20\ql million at the Closing to Casebia and is committed to contribute up to an additional $255 million in additional funds over time to\plain\cf1\f51\fs20\ql fund the operations of Casebia, subject to the conditions and procedures discussed below. We and Bayer HealthCare each hold a\plain\cf1\f51\fs20\ql 50%, non-transferable interest in Casebia.\par\pard\plain\sb264\cf1\f51\fs20\qc 19\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Casebia\u8217?s initial focus will be within the areas of hematology, ophthalmology and cardiology and autoimmune\plain\cf1\f51\fs20\ql diseases, in addition to select indications related to other sensory organs and metabolic diseases. Within these areas of focus, we\plain\cf1\f51\fs20\ql and Bayer HealthCare each have exclusive rights to specified disease indications, the CRISPR Field and Bayer Field,\plain\cf1\f51\fs20\ql respectively, as discussed below.\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Governance\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql In November of 2016, Casebia appointed James Burns as chief executive officer, or CEO, of Casebia, replacing Axel\plain\cf1\f51\fs20\ql Bouchon, the head of LifeScience Center of Bayer AG, who was serving as interim CEO. Dr. Burns also joined the Casebia\plain\cf1\f51\fs20\ql Board as a non-voting member. Casebia is generally governed by a management board, or the Management Board, which is\plain\cf1\f51\fs20\ql comprised of six voting members, three of which are designated by us and three of which are designated by Bayer. We have\plain\cf1\f51\fs20\ql designated Drs. Novak, Kulkarni and Ho to serve as our designees to the Management Board. Decisions of the Management\plain\cf1\f51\fs20\ql Board are generally made by majority vote, with each member having one vote. Certain matters require the consent of Bayer\plain\cf1\f51\fs20\ql HealthCare and us.\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Budget and Funding\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql The JV Agreement sets forth the initial 24-month budget for Casebia, which will be revised by the Management Board on\plain\cf1\f51\fs20\ql a yearly basis for the following 24 months. Bayer HealthCare, subject to certain conditions, is solely responsible for providing\plain\cf1\f51\fs20\ql Casebia with the necessary additional funding as determined by the Management Board until the earlier of (i) its aggregate\plain\cf1\f51\fs20\ql additional commitment amount of $255 million is fully funded, at which point all additional financing must be approved by the\plain\cf1\f51\fs20\ql Management Board or (ii) the termination of the JV Agreement in accordance with its terms. Any additional funding beyond the\plain\cf1\f51\fs20\ql amounts initially committed by Bayer HealthCare in the JV Agreement up to the $300 million aggregate commitment amount,\plain\cf1\f51\fs20\ql whether for purposes of an acquisition or otherwise, will not affect or dilute our 50% interest in Casebia.\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Non-Competition\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql During the term of the JV Agreement, neither we nor Bayer HealthCare, nor any of our respective affiliates, may develop,\plain\cf1\f51\fs20\ql commercialize or otherwise exploit any competing product utilizing the CRISPR/Cas technology in any of the Casebia Fields\plain\cf1\f51\fs20\ql unless, in the case of CRISPR or one of our affiliates, a target is the subject of a pre-existing license or an approved third-party\plain\cf1\f51\fs20\ql agreement, or certain other excluded targets. In addition, in the event either we, Bayer HealthCare or a third party license a\plain\cf1\f51\fs20\ql product candidate from Casebia pursuant to the Option Agreement discussed below, the non-licensing party or parties to the JV\plain\cf1\f51\fs20\ql Agreement will be prohibited from developing, commercializing or otherwise exploiting any product utilizing CRISPR/Cas\plain\cf1\f51\fs20\ql technology to target the same target as that of the licensed product candidate in any of the fields covered by such Option\plain\cf1\f51\fs20\ql Agreement, so long as the licensing party is clinically developing, commercializing or otherwise exploiting such licensed product\plain\cf1\f51\fs20\ql candidate.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Furthermore, upon a termination by either party for specified breaches of the other party, the defaulting party will be\plain\cf1\f51\fs20\ql prohibited from utilizing the CRISPR/Cas technology to develop, commercialize or otherwise exploit product candidates in the\plain\cf1\f51\fs20\ql field of the terminating party which would be competitive with the terminating party, for a period of two years following such\plain\cf1\f51\fs20\ql termination.\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Termination\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql The JV Agreement can be terminated by Bayer HealthCare and us upon mutual written consent. Either party may terminate\plain\cf1\f51\fs20\ql the JV Agreement in the event of specified breaches by the other party or in the event the other party becomes subject to\plain\cf1\f51\fs20\ql specified bankruptcy, winding up or similar circumstances. Either party may also terminate upon a change of control of the other\plain\cf1\f51\fs20\ql party, as defined in the JV Agreement. Bayer HealthCare also has the right to terminate in the event (i) we are not able to\plain\cf1\f51\fs20\ql maintain the intellectual property rights licensed to Casebia pursuant to the CRISPR IP Contribution Agreement or (ii) we have\plain\cf1\f51\fs20\ql not achieved preclinical proof of concept with a CRISPR/Cas9 product candidate in a specified period of time. The JV\plain\cf1\f51\fs20\ql Agreement may also be terminated by either party if, subsequent to the time that Bayer HealthCare has funded its entire $300\plain\cf1\f51\fs20\ql million commitment, the Management Board is unable to approve and obtain sufficient funding, within the time specified in the\plain\cf1\f51\fs20\ql JV Agreement, to continue Casebia\u8217?s operations for the next 18 months.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Subject to certain exceptions, in the event of a termination, all Casebia owned patents, know-how and technology will be\plain\cf1\f51\fs20\ql jointly owned by us and Bayer HealthCare, with the right to sublicense. Upon termination, subject to certain exceptions, Bayer\plain\cf1\f51\fs20\ql HealthCare will receive an exclusive license to Casebia CRISPR/Cas technology for all non-human therapeutic uses in the Bayer\plain\cf1\f51\fs20\ql Field and a non-exclusive license for human therapeutic uses. Upon such termination, we will receive an exclusive license to\plain\cf1\f51\fs20\ql Casebia CRISPR/Cas technology in human therapeutic areas, other than in the Bayer Field, and a non-exclusive license for\plain\cf1\f51\fs20\ql human therapeutic uses in the Bayer Field. Upon any termination, all rights licensed to Casebia pursuant to the CRISPR IP\plain\cf1\f51\fs20\ql Contribution Agreement will terminate, except for any rights licensed to third parties or to a party who has exercised an option\plain\cf1\f51\fs20\ql pursuant to the Option Agreement described below.\par\pard\plain\sb264\cf1\f51\fs20\qc 20\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql IP Contribution Agreement with Casebia\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql As part of our contribution to Casebia, in March 2016, we and certain of our affiliates entered into the CRISPR IP\plain\cf1\f51\fs20\ql Contribution Agreement with Casebia. Pursuant to the CRISPR IP Contribution Agreement, we and certain of our affiliated\plain\cf1\f51\fs20\ql entities granted Casebia an exclusive, worldwide, fully paid-up, royalty-free license, including the right to sublicense, to the use\plain\cf1\f51\fs20\ql of our CRISPR/Cas technology to research, develop, produce, commercialize and sell products in the Casebia Fields. As partial\plain\cf1\f51\fs20\ql consideration for the license, Casebia is required to pay us an aggregate amount of $35 million for a technology access fee,\plain\cf1\f51\fs20\ql consisting of an upfront payment of $20 million, which was paid at the closing of the JV Agreement in March 2016, and another\plain\cf1\f51\fs20\ql payment of $15 million when we obtain specified intellectual property rights relating to our CRISPR/Cas9 technology outside of\plain\cf1\f51\fs20\ql the United States, which was paid in December 2016 upon the signing of the IMA. The CRISPR IP Contribution Agreement also\plain\cf1\f51\fs20\ql contains license grants from Casebia to us to various forms of intellectual property developed or in-licensed by Casebia. The\plain\cf1\f51\fs20\ql CRISPR IP Contribution Agreement will terminate simultaneously with the termination of the JV Agreement, subject to survival\plain\cf1\f51\fs20\ql of certain licenses granted during the term, including licenses granted pursuant to an exercise of an option pursuant to the Option\plain\cf1\f51\fs20\ql Agreement.\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql Option Agreement with Bayer\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql In connection with the Closing, in March 2016, we, Bayer HealthCare and Casebia entered into an Option Agreement.\plain\cf1\f51\fs20\ql Pursuant to the Option Agreement, in the event the FDA accepts an IND submitted by Casebia for any product candidate it is\plain\cf1\f51\fs20\ql developing, both we and Bayer HealthCare have the right to submit an offer to enter into a license with Casebia for the exclusive\plain\cf1\f51\fs20\ql right to develop, manufacture and commercialize the product candidate in certain Casebia Fields. In addition, Casebia is allowed\plain\cf1\f51\fs20\ql to receive and consider unsolicited third-party offers, and both we and Bayer HealthCare can require Casebia to seek third-party\plain\cf1\f51\fs20\ql offers for the applicable product candidate. The Option Agreement sets forth the procedures the Management Board will follow\plain\cf1\f51\fs20\ql when considering and voting on any offers as well as the considerations on how to value any offer.\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql Collaboration Agreement with Vertex\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql On October\~26, 2015, we entered into a Strategic Collaboration, Option and License Agreement, or the Collaboration\plain\cf1\f51\fs20\ql Agreement, with Vertex Pharmaceuticals, Incorporated and Vertex Pharmaceuticals (Europe) Limited, together, Vertex. Pursuant\plain\cf1\f51\fs20\ql to the Collaboration Agreement, we agreed to provide technology and options to obtain licenses relating to our CRISPR/Cas\plain\cf1\f51\fs20\ql technology to Vertex in exchange for a $75 million upfront payment. In connection with the Collaboration Agreement, Vertex\plain\cf1\f51\fs20\ql also made a $30 million equity investment in us. Under the Collaboration Agreement, Vertex has the option to exclusively\plain\cf1\f51\fs20\ql license treatments for up to six collaboration targets that emerge from the four-year research collaboration under certain of our\plain\cf1\f51\fs20\ql platform and background intellectual property to develop, manufacture, commercialize, sell and use therapeutics directed to each\plain\cf1\f51\fs20\ql such collaboration target. For any non-hemoglobinopathies targets in-licensed for development, Vertex will pay future\plain\cf1\f51\fs20\ql development, regulatory and sales milestones of up to\~$420 million\~per target, as well as royalty payments in the single digits to\plain\cf1\f51\fs20\ql low teens on future sales of a commercialized product candidate. The milestone and royalty payments are each subject to\plain\cf1\f51\fs20\ql reduction under certain specified conditions set forth in the Collaboration Agreement. For these therapies, Vertex is solely\plain\cf1\f51\fs20\ql responsible for all research, development, manufacturing and global commercialization activities. Matters relating to\plain\cf1\f51\fs20\ql hemoglobinopathies targets our governed by the JDA we have with Vertex, as summarized below\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The initial focus of the Vertex collaboration will be to use CRISPR/Cas9 technology to discover and develop gene-based\plain\cf1\f51\fs20\ql treatments for hemoglobinopathies and cystic fibrosis. Further discovery efforts focused on a specified number of other genetic\plain\cf1\f51\fs20\ql targets will also be conducted under the Collaboration Agreement. We will be responsible for discovery activities, and the related\plain\cf1\f51\fs20\ql expenses will be fully funded by Vertex. Under the Collaboration Agreement, we and Vertex have each agreed to certain\plain\cf1\f51\fs20\ql exclusivity obligations with respect to targets subject to the Collaboration Agreement.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Either party can terminate the Collaboration Agreement upon the other party\u8217?s material breach, subject to specified\plain\cf1\f51\fs20\ql notice and cure provisions. Vertex also has the right to terminate the Collaboration Agreement for convenience at any time upon\plain\cf1\f51\fs20\ql 90 days\u8217? written notice prior to any product receiving marketing approval and upon 270 days\u8217? notice after a\plain\cf1\f51\fs20\ql product has received marketing approval. In the event we and Vertex make a filing under the Hart-Scott-Rodino Antitrust\plain\cf1\f51\fs20\ql Improvements Act of 1976, as amended, for a collaboration target and such filing is not cleared within a specified time after such\plain\cf1\f51\fs20\ql filing, the Collaboration Agreement will terminate with respect to that target. We may also terminate the Collaboration\plain\cf1\f51\fs20\ql Agreement in the event Vertex challenges any of our patent rights.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Absent early termination, the Collaboration Agreement will continue until the expiration of the Vertex\u8217?s payment\plain\cf1\f51\fs20\ql obligations under the Collaboration Agreement. Upon termination, the targets that are not licensed by Vertex will be returned to\plain\cf1\f51\fs20\ql us.\par\pard\plain\sb264\cf1\f51\fs20\qc 21\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In connection with entering into the JDA on December 12, 2017, we and Vertex entered into Amendment No.\~1 to the\plain\cf1\f51\fs20\ql Collaboration Agreement, or the Amendment. The Amendment, among other things, modified certain definitions and provisions\plain\cf1\f51\fs20\ql of the Collaboration Agreement to make them consistent with the JDA and clarified how many options are exercised (or deemed\plain\cf1\f51\fs20\ql exercised) in connection with certain targets specified under the Collaboration Agreement. The Amendment also amended other\plain\cf1\f51\fs20\ql provisions of the Collaboration Agreement, including the expiration terms of the Collaboration Agreement.\par\pard\plain\sb396\fi264\cf1\f51\fs20\b\i\ql Joint Development Agreement with Vertex\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql On December 12, 2017, we entered into the JDA with Vertex. The initial focus of the JDA is for the development of\plain\cf1\f51\fs20\ql CTX001 for beta-thalassemia and SCD. In connection with entering into the JDA, we received a $7.0 million up-front payment\plain\cf1\f51\fs20\ql from Vertex and are eligible for a one-time low seven-digit milestone payment upon the dosing of the second patient in a\plain\cf1\f51\fs20\ql clinical trial with the initial product candidate. The net profits and net losses, as applicable, incurred under the JDA will be\plain\cf1\f51\fs20\ql shared equally between us and Vertex.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The JDA includes, among other things, provisions relating to the following:\par\pard\plain\sb264\fi528\cf1\f51\fs20\i\ql Governance.\~\plain\cf1\f51\fs20\ql CRISPR and Vertex will form the following committees: (i)\~a joint steering committee to provide high-level\plain\cf1\f51\fs20\ql oversight and decision making regarding the activities covered by the JDA, (ii)\~a joint development committee to provide\plain\cf1\f51\fs20\ql oversight and decision making-making regarding development activities, (iii)\~a joint commercialization committee to provide\plain\cf1\f51\fs20\ql oversight and decision-making regarding commercialization activities and (iv)\~a joint manufacturing committee to provide\plain\cf1\f51\fs20\ql oversight and decision-making regarding manufacturing activities. Each of the committees will contain an equal number of\plain\cf1\f51\fs20\ql representatives from each of CRISPR and Vertex.\par\pard\plain\sb264\fi528\cf1\f51\fs20\i\ql Commercialization.\plain\cf1\f51\fs20\ql \~The JDA provides that we will be the responsible for commercialization activities in the United States\plain\cf1\f51\fs20\ql and Vertex will be responsible for commercialization activities outside of the United States.\par\pard\plain\sb264\fi528\cf1\f51\fs20\i\ql Termination.\plain\cf1\f51\fs20\ql \~Either party can terminate the JDA upon the other party\u8217?s material breach, subject to specified notice\plain\cf1\f51\fs20\ql and cure provisions, or, in the case of Vertex, in the event that we become subject to specified bankruptcy, winding up or similar\plain\cf1\f51\fs20\ql circumstances. Either party may terminate the JDA in the event the other party commences or participates in any action or\plain\cf1\f51\fs20\ql proceeding challenging the validity or enforceability of any patent that is licensed to such challenging party pursuant to the JDA.\plain\cf1\f51\fs20\ql Vertex also has the right to terminate the JDA for convenience at any time after giving prior written notice.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql If circumstances arise pursuant to which a party would have the right to terminate the JDA on account of an uncured\plain\cf1\f51\fs20\ql material breach, such party may elect to keep the JDA in effect and cause such breaching party to be treated as if it had\plain\cf1\f51\fs20\ql exercised its\~opt-out\~rights with respect to the products associated with such uncured material breach (described below) and the\plain\cf1\f51\fs20\ql royalties payable to the breaching party would be reduced by a specified percentage.\par\pard\plain\sb264\fi528\cf1\f51\fs20\i\ql Opt-Out\~Rights\plain\cf1\f51\fs20\ql . Either party may opt of out of the development of a product candidate under the JDA after predetermined\plain\cf1\f51\fs20\ql points in the development of the product candidate, on a\~candidate-by-candidate\~basis. In the event of such\~opt-out,\~the\plain\cf1\f51\fs20\ql party\~opting-out\~will no longer share in the net profits and net losses associated with such product candidate and, instead, the\plain\cf1\f51\fs20\ql opting out party will be entitled to high single to\~mid-\~teen percentage royalties on the net sales of such product, if\plain\cf1\f51\fs20\ql commercialized.\par\pard\plain\sb396\cf1\f51\fs20\b\ql Manufacturing\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We have entered into certain manufacturing and supply arrangements with third-party suppliers to support production of\plain\cf1\f51\fs20\ql our product candidates and their components. We plan to continue to rely on qualified third-party organizations to produce or\plain\cf1\f51\fs20\ql process bulk compounds, formulated compounds, viral vectors or engineered cells for IND-supporting activities and early stage\plain\cf1\f51\fs20\ql clinical trials. We expect that commercial quantities of any compound, vector, or engineered cells that we may seek to develop\plain\cf1\f51\fs20\ql will be manufactured in facilities and by processes that comply with FDA and other regulations. At the appropriate time in the\plain\cf1\f51\fs20\ql product development process, we will determine whether to establish manufacturing facilities or continue to rely on third parties\plain\cf1\f51\fs20\ql to manufacture commercial quantities of any products that we may successfully develop. Outside of the United States and\plain\cf1\f51\fs20\ql Europe, where appropriate, we may elect in the future to utilize strategic partners, distributors or contract sales forces to assist in\plain\cf1\f51\fs20\ql the commercialization of our products. In certain instances, we may consider building our own commercial infrastructure.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql As product candidates advance through our pipeline, our commercial plans may change. In particular, some of our research\plain\cf1\f51\fs20\ql programs target potentially larger indications. Data, the size of the development programs, the size of the target market, the size\plain\cf1\f51\fs20\ql of a commercial infrastructure and manufacturing needs may all influence our strategies in the United States, Europe and the rest\plain\cf1\f51\fs20\ql of the world.\par\pard\plain\sb264\cf1\f51\fs20\qc 22\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb396\cf1\f51\fs20\b\ql Competition\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql The biotechnology and pharmaceutical industries, including in the gene therapy and gene editing fields, are characterized by\plain\cf1\f51\fs20\ql rapidly advancing technologies, intense competition, and a strong emphasis on intellectual property and proprietary products.\plain\cf1\f51\fs20\ql While we believe that our technology, development experience, and scientific knowledge provide us with competitive advantages,\plain\cf1\f51\fs20\ql we currently face, and will continue to face, competition from many different sources, including major pharmaceutical, specialty\plain\cf1\f51\fs20\ql pharmaceutical, and biotechnology companies, academic institutions and governmental agencies, and public and private research\plain\cf1\f51\fs20\ql institutions. For any products that we may ultimately commercialize, not only will we compete with any existing therapies and\plain\cf1\f51\fs20\ql those therapies currently in development, we will have to compete with new therapies that may become available in the future.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We compete in the segments of the pharmaceutical, biotechnology, and other related markets that utilize technologies\plain\cf1\f51\fs20\ql encompassing genomic medicines to create therapies, including gene editing and gene therapy. There are additional companies\plain\cf1\f51\fs20\ql that are working to develop therapies in areas related to our research programs.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Our platform and product focus is on the development of therapies using CRISPR/Cas9 technology. Other companies\plain\cf1\f51\fs20\ql developing CRISPR/Cas9 technology include Intellia and Editas Medicine, Inc.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql There are additional companies developing therapies using additional gene-editing technologies, including TALENs,\plain\cf1\f51\fs20\ql meganucleases, and zinc finger nucleases. The companies developing these additional gene-editing technologies include bluebird\plain\cf1\f51\fs20\ql bio, Cellectis, Poseida Therapeutics, Precision Biosciences, and Sangamo Biosciences. Additional companies developing gene\plain\cf1\f51\fs20\ql therapy products include Abeona Therapeutics, Avalanche Biotechnologies, Dimension Therapeutics, REGENXBIO, Spark\plain\cf1\f51\fs20\ql Therapeutics and uniQure. In addition to competition from other gene-editing therapies or gene therapies, any products that we\plain\cf1\f51\fs20\ql develop may also face competition from other types of therapies, such as small molecule, antibody, or protein therapies.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We may also face future competition from newly discovered gene editing technologies or new CRISPR-associated\plain\cf1\f51\fs20\ql nucleases. While we believe that CRISPR/Cas9 will be highly effective for many therapeutic applications and are actively\plain\cf1\f51\fs20\ql working to further enhance the technology, more efficient gene editing technologies may emerge. For example, recent\plain\cf1\f51\fs20\ql publications by Feng Zhang, Ph.D., one of the founders of Editas Medicine, Inc. and others have elucidated a different\plain\cf1\f51\fs20\ql CRISPR-associated nuclease, Cpf1, which can also edit human DNA. Some have argued that Cpf1 is superior to Cas9 for certain\plain\cf1\f51\fs20\ql applications. Gene editing is a highly active field of research and new technologies, related or unrelated to CRISPR, may be\plain\cf1\f51\fs20\ql discovered and create new competition.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In addition, many of our current or potential competitors, either alone or with their collaboration partners, have significantly\plain\cf1\f51\fs20\ql greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials,\plain\cf1\f51\fs20\ql and marketing approved products than we do. Mergers and acquisitions in the pharmaceutical, biotechnology, and gene therapy\plain\cf1\f51\fs20\ql industries may result in even more resources being concentrated among a smaller number of our competitors. Smaller or\plain\cf1\f51\fs20\ql early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large\plain\cf1\f51\fs20\ql and established companies. These competitors also compete with us in recruiting and retaining qualified scientific and\plain\cf1\f51\fs20\ql management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring\plain\cf1\f51\fs20\ql technologies complementary to, or necessary for, our programs. Our commercial opportunity could be reduced or eliminated if\plain\cf1\f51\fs20\ql our competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are\plain\cf1\f51\fs20\ql more convenient or are less expensive than any products that we may develop. Our competitors also may obtain FDA or other\plain\cf1\f51\fs20\ql regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors\plain\cf1\f51\fs20\ql establishing a strong market position before we are able to enter the market. The key competitive factors affecting the success of\plain\cf1\f51\fs20\ql all of our programs are likely to be their efficacy, safety, convenience, and availability of reimbursement.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql If our current programs are approved for the indications for which we are currently planning clinical trials, they may\plain\cf1\f51\fs20\ql compete with other products currently under development, including gene editing and gene therapy products. Competition with\plain\cf1\f51\fs20\ql other related products currently under development may include competition for clinical trial sites, patient recruitment, and\plain\cf1\f51\fs20\ql product sales.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In addition, due to the intense research and development that is taking place by several companies, including us and our\plain\cf1\f51\fs20\ql competitors, in the gene editing field, the intellectual property landscape is in flux and highly competitive. There may be\plain\cf1\f51\fs20\ql significant intellectual property related litigation and proceedings, in addition to the ongoing interference proceedings, relating to\plain\cf1\f51\fs20\ql our owned and in-licensed, and other third party, intellectual property and proprietary rights in the future.{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql For example, in January 2016, at our request, the USPTO declared an interference between one of the pending U.S. patent\plain\cf1\f51\fs20\ql applications we licensed from Dr. Emmanuelle Charpentier and twelve issued U.S. patents, and subsequently added one U.S.\plain\cf1\f51\fs20\ql patent application, owned jointly by Broad. Because our application was filed first, the USPTO designated Dr. Charpentier,\plain\cf1\f51\fs20\ql California and Vienna, or Vienna, collectively as \u8220?Senior Party\u8221? and designated Broad as \u8220?Junior\plain\cf1\f51\fs20\ql Party.\u8221? Following motions by the parties and other procedural matters, the PTAB concluded in February 2017 that the\plain\cf1\f51\fs20\ql declared interference should be dismissed because the claim sets of\par\pard\plain\sb264\cf1\f51\fs20\qc 23\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb264\cf1\f51\fs20\ql the two parties were not directed to the same patentable invention in accordance with the PTAB\u8217?s two-way test for patent\plain\cf1\f51\fs20\ql interferences. In particular, the Junior Party\u8217?s claims in the interference were all limited to uses in eukaryotic cells, while\plain\cf1\f51\fs20\ql the Senior Party\u8217?s claims in the interference were not limited to uses in eukaryotic cells but included uses in all settings.\plain\cf1\f51\fs20\ql Senior Party has appealed the decision to the U.S. Court of Appeals for the Federal Circuit. In parallel, either party can also\plain\cf1\f51\fs20\ql pursue existing or new patent applications in the U.S. and elsewhere. Going forward, either party as well as other parties could\plain\cf1\f51\fs20\ql seek a new interference related to the uses of the technology in eukaryotic cells or other aspects of the technology, and any\plain\cf1\f51\fs20\ql existing or new patents could be the subject of other challenges to their validity of enforceability. In the context of a second\plain\cf1\f51\fs20\ql interference or in other proceedings, a determination could be reached regarding that the Senior Party was not the first to invent,\plain\cf1\f51\fs20\ql or it could be concluded that the contested subject matter is not patentable to the Senior Party and is patentable to the Junior\plain\cf1\f51\fs20\ql Party, which in this case could preclude our U.S. patent applications from issuing as patents, in which case the proceedings\plain\cf1\f51\fs20\ql would result in our losing the right to protect core innovations and our freedom to practice our core gene editing technology. If\plain\cf1\f51\fs20\ql there is a second interference, either party could again appeal an adverse decision to the U.S. Court of Appeals for the Federal\plain\cf1\f51\fs20\ql Circuit. In any case, it may be years before there is a final determination on priority. For example, Toolgen Inc., or Toolgen,\plain\cf1\f51\fs20\ql filed Suggestions of Interference in the USPTO on April 13, 2015 and December 3, 2015, suggesting that they believe some of\plain\cf1\f51\fs20\ql the claims in pending U.S. applications owned by Toolgen (U.S. Serial No. 14/685,568 and U.S. Serial No. 14/685,510,\plain\cf1\f51\fs20\ql respectively) interfere with certain claims in five of the Broad patents currently involved in the interference with Dr. Emmanuelle\plain\cf1\f51\fs20\ql Charpentier, California and Vienna. We are also aware of additional third parties that have pending patent applications relating to\plain\cf1\f51\fs20\ql CRISPR technologies, which similarly may lead to further interference proceedings. For example, Rockefeller University has filed\plain\cf1\f51\fs20\ql a continuation application (U.S. Serial No. 14/324,960) of an application filed by the Broad that Rockefeller\u8217?s employee\plain\cf1\f51\fs20\ql Luciano Marraffini as co-inventor of CRISPR/Cas9 technology; Vilnius University has filed applications in the United States and\plain\cf1\f51\fs20\ql in other jurisdictions (published internationally as WO2013/141680 and WO2013/142578), Harvard University has filed\plain\cf1\f51\fs20\ql applications in the United States and in other jurisdictions (published internationally as WO2014/099744), and Sigma-Aldrich has\plain\cf1\f51\fs20\ql filed applications in the United States and in other jurisdictions (published internationally as WO2014/089290), each claiming\plain\cf1\f51\fs20\ql aspects of CRISPR/Cas9 technology based on applications claiming priority to provisional filings in 2012. Numerous other filings\plain\cf1\f51\fs20\ql are based on provisional applications filed after 2012.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Broad, Toolgen and Sigma have filed international counterparts of their U.S. applications, some of which were granted in\plain\cf1\f51\fs20\ql Europe and/or other jurisdictions. We and third parties have initiated opposition proceedings against some of these grants, and we\plain\cf1\f51\fs20\ql may in the future oppose other grants to these or other applicants. Similarly, if we should obtain patent grants in the U.S., Europe\plain\cf1\f51\fs20\ql and other jurisdictions, these could also be the subject of oppositions or other post-grant procedures sought by third parties in\plain\cf1\f51\fs20\ql order to revoke the grants or narrow the scope of granted claims. For example, our first patent granted in Europe has been\plain\cf1\f51\fs20\ql opposed by multiple parties. Going forward, with existing and new challenges being filed against CRISPR/Cas9 cases in the U.S.,\plain\cf1\f51\fs20\ql Europe and elsewhere, and considering the number of interested parties, it is reasonable to expect that patents directed to the\plain\cf1\f51\fs20\ql underlying technology will continue to be the subject of ongoing disputes over at least the next several years, and potentially\plain\cf1\f51\fs20\ql beyond as decisions in favor or against particular parties may be the subject of appeals.\par\pard\plain\sb396\cf1\f51\fs20\b\ql Government Regulation\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Government authorities in the United States, at the federal, state and local level, and in other countries and jurisdictions,\plain\cf1\f51\fs20\ql including the European Union, extensively regulate, among other things, the research, development, testing, manufacture, quality\plain\cf1\f51\fs20\ql control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval\plain\cf1\f51\fs20\ql monitoring and reporting, and import and export of pharmaceutical products, including biological products. Some jurisdictions\plain\cf1\f51\fs20\ql outside of the United States also regulate the pricing of such products. The processes for obtaining marketing approvals in the\plain\cf1\f51\fs20\ql United States and in other countries and jurisdictions, along with subsequent compliance with applicable statutes and regulations\plain\cf1\f51\fs20\ql and other regulatory authorities, require the expenditure of substantial time and financial resources.\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql Licensure and Regulation of Biologics in the United States\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql In the United States, our candidate products would be regulated as biological products, or biologics, under the Public\plain\cf1\f51\fs20\ql Health Service Act, or PHSA, and the Federal Food, Drug, and Cosmetic Act, or FDCA, and their implementing regulations. The\plain\cf1\f51\fs20\ql failure to comply with the applicable U.S. requirements at any time during the product development process, including\plain\cf1\f51\fs20\ql nonclinical testing, clinical testing, the approval process or post-approval process, may subject an applicant to delays in the\plain\cf1\f51\fs20\ql conduct of a study, regulatory review and approval, and/or administrative or judicial sanctions. These sanctions may include, but\plain\cf1\f51\fs20\ql are not limited to, the FDA\u8217?s refusal to allow an applicant to proceed with clinical testing, refusal to approve pending\plain\cf1\f51\fs20\ql applications, license suspension or revocation, withdrawal of an approval, untitled or warning letters, adverse publicity, product\plain\cf1\f51\fs20\ql recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, and civil or criminal\plain\cf1\f51\fs20\ql investigations and penalties brought by the FDA or the Department of Justice, or DOJ, or other governmental entities.\par\pard\plain\sb264\cf1\f51\fs20\qc 24\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql An applicant seeking approval to market and distribute a new biologic in the United States generally must satisfactorily\plain\cf1\f51\fs20\ql complete each of the following steps:
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\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql preclinical laboratory tests, animal studies and formulation studies all performed in accordance with the\plain\intbl\cf1\f51\fs20\ql FDA\u8217?s Good Laboratory Practice, or GLP, regulations;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql submission to the FDA of an IND application for human clinical testing, which must become effective before\plain\intbl\cf1\f51\fs20\ql human clinical trials may begin;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql approval by an independent institutional review board, or IRB, representing each clinical site before each clinical\plain\intbl\cf1\f51\fs20\ql trial may be initiated, or by a central IRB if appropriate;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh878
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql performance of adequate and well-controlled human clinical trials to establish the safety, potency, and purity of the\plain\intbl\cf1\f51\fs20\ql product candidate for each proposed indication, in accordance with the FDA\u8217?s Good Clinical Practice, or\plain\intbl\cf1\f51\fs20\ql GCP, regulations;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh878
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql preparation and submission to the FDA of a Biologics License Application, or BLA, for a biologic product\plain\intbl\cf1\f51\fs20\ql requesting marketing for one or more proposed indications, including submission of detailed information on the\plain\intbl\cf1\f51\fs20\ql manufacture and composition of the product and proposed labeling;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh878\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql review of the product by an FDA advisory committee, where appropriate or if applicable;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh1372
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities, including those\plain\intbl\cf1\f51\fs20\ql of third parties, at which the product, or components thereof, are produced to assess compliance with cGMP\plain\intbl\cf1\f51\fs20\ql requirements and to assure that the facilities, methods, and controls are adequate to preserve the product\u8217?s\plain\intbl\cf1\f51\fs20\ql identity, strength, quality, and purity, and, if applicable, the FDA\u8217?s current good tissue practice, or CGTP, for\plain\intbl\cf1\f51\fs20\ql the use of human cellular and tissue products;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql satisfactory completion of any FDA audits of the nonclinical study and clinical trial sites to assure compliance with\plain\intbl\cf1\f51\fs20\ql GLPs and GCPs, respectively, and the integrity of clinical data in support of the BLA;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql payment of user fees and securing FDA approval of the BLA; and\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh878
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql compliance with any post-approval requirements, including the potential requirement to implement a Risk\plain\intbl\cf1\f51\fs20\ql Evaluation and Mitigation Strategy, or REMS, adverse event reporting, and compliance with any post-approval\plain\intbl\cf1\f51\fs20\ql studies required by the FDA.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh878\row}}}\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Preclinical Studies and Investigational New Drug Application\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Before testing any biologic product candidate in humans, including a gene therapy product candidate, the product candidate\plain\cf1\f51\fs20\ql must undergo preclinical testing. Preclinical tests include laboratory evaluations of product chemistry, formulation and stability, as\plain\cf1\f51\fs20\ql well as studies to evaluate the potential for efficacy and toxicity in animals. The conduct of the preclinical tests and formulation\plain\cf1\f51\fs20\ql of the compounds for testing must comply with federal regulations and requirements. The results of the preclinical tests, together\plain\cf1\f51\fs20\ql with manufacturing information and analytical data, are submitted to the FDA as part of an IND application. The IND\plain\cf1\f51\fs20\ql automatically becomes effective 30\~days after receipt by the FDA, unless before that time the FDA imposes a clinical hold based\plain\cf1\f51\fs20\ql on concerns or questions about the product or conduct of the proposed clinical trial, including concerns that human research\plain\cf1\f51\fs20\ql subjects would be exposed to unreasonable and significant health risks. In that case, the IND sponsor and the FDA must resolve\plain\cf1\f51\fs20\ql any outstanding FDA concerns before the clinical trials can begin.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql As a result, submission of the IND may result in the FDA not allowing the trials to commence or allowing the trial to\plain\cf1\f51\fs20\ql commence on the terms originally specified by the sponsor in the IND. If the FDA raises concerns or questions either during this\plain\cf1\f51\fs20\ql initial 30-day period, or at any time during the conduct of the IND study, including safety concerns or concerns due to\plain\cf1\f51\fs20\ql non-compliance, it may impose a partial or complete clinical hold. This order issued by the FDA would delay either a proposed\plain\cf1\f51\fs20\ql clinical study or cause suspension of an ongoing study, until all outstanding concerns have been adequately addressed and the\plain\cf1\f51\fs20\ql FDA has notified the company that investigations may proceed or recommence but only under terms authorized by the FDA. This\plain\cf1\f51\fs20\ql could cause significant delays or difficulties in completing planned clinical studies in a timely manner.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql With gene therapy protocols, if the FDA allows the IND to proceed, but the Recombinant DNA Advisory Committee, or\plain\cf1\f51\fs20\ql RAC, of the National Institute of Health, or NIH, decides that full public review of the protocol is warranted, the FDA will\plain\cf1\f51\fs20\ql request at the completion of its IND review that sponsors delay initiation of the protocol until after completion of the RAC\plain\cf1\f51\fs20\ql review process.\par\pard\plain\sb264\cf1\f51\fs20\qc 25\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Human Clinical Trials in Support of a BLA\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Clinical trials involve the administration of the investigational product candidate to healthy volunteers or patients with the\plain\cf1\f51\fs20\ql disease to be treated under the supervision of a qualified principal investigator in accordance with GCP requirements. Clinical\plain\cf1\f51\fs20\ql trials are conducted under study protocols detailing, among other things, the objectives of the study, inclusion and exclusion\plain\cf1\f51\fs20\ql criteria, the parameters to be used in monitoring safety, and the effectiveness criteria to be evaluated. A protocol for each clinical\plain\cf1\f51\fs20\ql trial and subsequent protocol amendments must be submitted to the FDA as part of the IND.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql A sponsor who wishes to conduct a clinical trial outside the United States may, but need not, obtain FDA authorization to\plain\cf1\f51\fs20\ql conduct the clinical trial under an IND. If a non-U.S. clinical trial is not conducted under an IND, the sponsor may submit data\plain\cf1\f51\fs20\ql from a well-designed and well-conducted clinical trial to the FDA in support of the BLA so long as the clinical trial is\plain\cf1\f51\fs20\ql conducted in compliance with international guidelines for the ethical conduct of clinical research known as good clinical practice,\plain\cf1\f51\fs20\ql or GCP, and the FDA is able to validate the data from the study through an onsite inspection if the FDA deems it necessary.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Further, each clinical trial must be reviewed and approved by an independent institutional review board, or IRB, either\plain\cf1\f51\fs20\ql centrally or individually at each institution at which the clinical trial will be conducted. The IRB will consider, among other\plain\cf1\f51\fs20\ql things, clinical trial design, subject informed consent, ethical factors, and the safety of human subjects. An IRB must operate in\plain\cf1\f51\fs20\ql compliance with FDA regulations. The FDA or the clinical trial sponsor may suspend or terminate a clinical trial at any time for\plain\cf1\f51\fs20\ql various reasons, including a finding that the clinical trial is not being conducted in accordance with FDA requirements or the\plain\cf1\f51\fs20\ql subjects or patients are being exposed to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a\plain\cf1\f51\fs20\ql clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB\u8217?s requirements or if the\plain\cf1\f51\fs20\ql drug has been associated with unexpected serious harm to patients. Clinical testing also must satisfy extensive GCP rules and the\plain\cf1\f51\fs20\ql requirements for informed consent. Additionally, some clinical trials are overseen by an independent group of qualified experts\plain\cf1\f51\fs20\ql organized by the clinical trial sponsor, known as a data safety monitoring board or committee. This group may recommend\plain\cf1\f51\fs20\ql continuation of the study as planned, changes in study conduct, or cessation of the study at designated check points based on\plain\cf1\f51\fs20\ql access to certain data from the study. Finally, research activities involving infectious agents, hazardous chemicals, recombinant\plain\cf1\f51\fs20\ql DNA, and genetically altered organisms and agents may be subject to review and approval of an Institutional Biosafety\plain\cf1\f51\fs20\ql Committee established under the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Clinical trials typically are conducted in three sequential phases, but the phases may overlap or be combined. Additional\plain\cf1\f51\fs20\ql studies may be required after approval.
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\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\b\i\ql Phase\~1\plain\intbl\cf1\f51\fs20\ql clinical trials are initially conducted in a limited population to test the product candidate for safety,\plain\intbl\cf1\f51\fs20\ql including adverse effects, dose tolerance, absorption, metabolism, distribution, excretion, and pharmacodynamics in\plain\intbl\cf1\f51\fs20\ql healthy humans or, on occasion, in patients, such as cancer patients.\cell{
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\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\b\i\ql Phase\~2\plain\intbl\cf1\f51\fs20\ql clinical trials are generally conducted in a limited patient population to identify possible adverse effects and\plain\intbl\cf1\f51\fs20\ql safety risks, evaluate the efficacy of the product candidate for specific targeted indications and determine dose\plain\intbl\cf1\f51\fs20\ql tolerance and optimal dosage. Multiple Phase\~2 clinical trials may be conducted by the sponsor to obtain\plain\intbl\cf1\f51\fs20\ql information prior to beginning larger and costlier Phase\~3 clinical trials.\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh878
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\b\i\ql Phase\~3\plain\intbl\cf1\f51\fs20\ql clinical trials are undertaken within an expanded patient population to further evaluate dosage and gather\plain\intbl\cf1\f51\fs20\ql the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk\plain\intbl\cf1\f51\fs20\ql relationship of the drug and to provide an adequate basis for physician labeling.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh878\row}}}\pard\plain\sb264\fi528\cf1\f51\fs20\ql Progress reports detailing the results, if known, of the clinical trials must be submitted at least annually to the FDA.\plain\cf1\f51\fs20\ql Written IND safety reports must be submitted to the FDA and the investigators within 15 calendar days after determining that the\plain\cf1\f51\fs20\ql information qualifies for reporting. IND safety reports are required for serious and unexpected suspected adverse events, findings\plain\cf1\f51\fs20\ql from other studies or animal or\plain\cf1\f51\fs20\i\ql in vitro\plain\cf1\f51\fs20\ql testing that suggest a significant risk to humans exposed to the drug, and any clinically\plain\cf1\f51\fs20\ql important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.\plain\cf1\f51\fs20\ql Additionally, a sponsor must notify FDA within 7 calendar days after receiving information concerning any unexpected fatal or\plain\cf1\f51\fs20\ql life-threatening suspected adverse reaction.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In some cases, the FDA may approve a BLA for a product candidate but require the sponsor to conduct additional clinical\plain\cf1\f51\fs20\ql trials to further assess the product candidate\u8217?s safety and effectiveness after approval. Such post-approval trials are\plain\cf1\f51\fs20\ql typically referred to as Phase\~4 clinical trials. These studies are used to gain additional experience from the treatment of patients\plain\cf1\f51\fs20\ql in the intended therapeutic indication and to document a clinical benefit in the case of biologics approved under accelerated\plain\cf1\f51\fs20\ql approval regulations. Failure to exhibit due diligence with regard to conducting Phase\~4 clinical trials could result in withdrawal\plain\cf1\f51\fs20\ql of approval for products.\par\pard\plain\sb264\cf1\f51\fs20\qc 26\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Special Regulations and Guidance Governing Gene Therapy Products\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql It is possible that the procedures and standards applied to gene therapy products and cell therapy products may be applied\plain\cf1\f51\fs20\ql to any CRISPR/Cas9 product candidates we may develop, but that remains uncertain at this point. The FDA has defined a gene\plain\cf1\f51\fs20\ql therapy product as one that mediates its effects by transcription and/or translation of transferred genetic material and/or by\plain\cf1\f51\fs20\ql integrating into the host genome and which are administered as nucleic acids, viruses, or genetically engineered microorganisms.\plain\cf1\f51\fs20\ql The products may be used to modify cells\plain\cf1\f51\fs20\i\ql in vivo\plain\cf1\f51\fs20\ql or transferred to cells\plain\cf1\f51\fs20\i\ql ex vivo\plain\cf1\f51\fs20\ql prior to administration to the recipient. Within\plain\cf1\f51\fs20\ql the FDA, the Center for Biologics Evaluation and Research, or CBER, regulates gene therapy products. Within the CBER, the\plain\cf1\f51\fs20\ql review of gene therapy and related products is consolidated in the Office of Tissues and Advanced Therapies, and the FDA has\plain\cf1\f51\fs20\ql established the Cellular, Tissue and Gene Therapies Advisory Committee to advise CBER on its reviews. The CBER works\plain\cf1\f51\fs20\ql closely with the NIH and the RAC, which makes recommendations to the NIH on gene therapy issues and engages in a public\plain\cf1\f51\fs20\ql discussion of scientific, safety, ethical, and societal issues related to proposed and ongoing gene therapy protocols. The FDA and\plain\cf1\f51\fs20\ql the NIH have published guidance documents with respect to the development and submission of gene therapy protocols.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Although the FDA has indicated that its guidance documents regarding gene therapies are not legally binding, we believe\plain\cf1\f51\fs20\ql that our compliance with them is likely necessary to gain approval for any product candidate we may develop. The guidance\plain\cf1\f51\fs20\ql documents provide additional factors that the FDA will consider at each of the above stages of development and relate to, among\plain\cf1\f51\fs20\ql other things, the proper preclinical assessment of gene therapies; the chemistry, manufacturing, and control information that\plain\cf1\f51\fs20\ql should be included in an IND application; the proper design of tests to measure product potency in support of an IND or BLA\plain\cf1\f51\fs20\ql application; and measures to observe delayed adverse effects in subjects who have been exposed to investigational gene therapies\plain\cf1\f51\fs20\ql when the risk of such effects is high. Further, the FDA usually recommends that sponsors observe subjects for potential gene\plain\cf1\f51\fs20\ql therapy-related delayed adverse events for a 15-year period, including a minimum of five years of annual examinations followed\plain\cf1\f51\fs20\ql by 10\~years of annual queries, either in person or by questionnaire.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql If a gene therapy trial is conducted at, or sponsored by, institutions receiving NIH funding for recombinant DNA research,\plain\cf1\f51\fs20\ql a protocol and related documentation must be submitted to, and the study registered with, the NIH Office of Biotechnology\plain\cf1\f51\fs20\ql Activities, or OBA, pursuant to the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules\plain\cf1\f51\fs20\ql prior to the submission of an IND to the FDA. In addition, many companies and other institutions not otherwise subject to the\plain\cf1\f51\fs20\ql NIH Guidelines voluntarily follow them. The NIH will convene the Recombinant DNA Advisory Committee, or RAC, a federal\plain\cf1\f51\fs20\ql advisory committee, to discuss protocols that raise novel or particularly important scientific, safety or ethical considerations at\plain\cf1\f51\fs20\ql one of its quarterly public meetings. The OBA will notify the FDA of the RAC\u8217?s decision regarding the necessity for full\plain\cf1\f51\fs20\ql public review of a gene therapy protocol. RAC proceedings and reports are posted to the OBA web site and may be accessed by\plain\cf1\f51\fs20\ql the public.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Finally, to facilitate adverse event reporting and dissemination of additional information about gene therapy trials, the FDA\plain\cf1\f51\fs20\ql and the NIH established the Genetic Modification Clinical Research Information System, or GeMCRIS. Investigators and\plain\cf1\f51\fs20\ql sponsors of a human gene transfer trials can utilize this web-based system to report serious adverse events and annual reports.\plain\cf1\f51\fs20\ql GeMCRIS also allows members of the public to access basic reports about human gene transfer trials registered with the NIH\plain\cf1\f51\fs20\ql and to search for information such as trial location, the names of investigators conducting trials, and the names of gene transfer\plain\cf1\f51\fs20\ql products being studied.\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Compliance with cGMP and CGTP Requirements\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Before approving a BLA, the FDA typically will inspect the facility or facilities where the product is manufactured. The\plain\cf1\f51\fs20\ql FDA will not approve an application unless it determines that the manufacturing processes and facilities are in full compliance\plain\cf1\f51\fs20\ql with cGMP requirements and adequate to assure consistent production of the product within required specifications. The PHSA\plain\cf1\f51\fs20\ql emphasizes the importance of manufacturing control for products like biologics whose attributes cannot be precisely defined.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql For a gene therapy product, the FDA also will not approve the product if the manufacturer is not in compliance with\plain\cf1\f51\fs20\ql CGTP. These requirements are found in FDA regulations that govern the methods used in, and the facilities and controls used\plain\cf1\f51\fs20\ql for, the manufacture of human cells, tissues, and cellular and tissue-based products, or HCT/Ps, which are human cells or tissue\plain\cf1\f51\fs20\ql intended for implantation, transplant, infusion, or transfer into a human recipient. The primary intent of the CGTP requirements is\plain\cf1\f51\fs20\ql to ensure that cell and tissue-based products are manufactured in a manner designed to prevent the introduction, transmission,\plain\cf1\f51\fs20\ql and spread of communicable disease. FDA regulations also require tissue establishments to register and list their HCT/Ps with the\plain\cf1\f51\fs20\ql FDA and, when applicable, to evaluate donors through screening and testing.\par\pard\plain\sb264\cf1\f51\fs20\qc 27\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Manufacturers and others involved in the manufacture and distribution of products must also register their establishments\plain\cf1\f51\fs20\ql with the FDA and certain state agencies for products intended for the U.S. market, and with analogous health regulatory agencies\plain\cf1\f51\fs20\ql for products intended for other markets globally. Both U.S. and non-U.S. manufacturing establishments must register and provide\plain\cf1\f51\fs20\ql additional information to the FDA and/or other health regulatory agencies upon their initial participation in the manufacturing\plain\cf1\f51\fs20\ql process. Any product manufactured by or imported from a facility that has not registered, whether U.S. or non-U.S., is deemed\plain\cf1\f51\fs20\ql misbranded under the FDCA, and could be affected by similar as well as additional compliance issues in other jurisdictions.\plain\cf1\f51\fs20\ql Establishments may be subject to periodic unannounced inspections by government authorities to ensure compliance with\plain\cf1\f51\fs20\ql cGMP\u8217?s and other laws. Manufacturers may also have to provide, on request, electronic or physical records regarding their\plain\cf1\f51\fs20\ql establishments. Delaying, denying, limiting, or refusing inspection by the FDA or other governing health regulatory agency may\plain\cf1\f51\fs20\ql lead to a product being deemed to be adulterated.\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Review and Approval of a BLA\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql The results of product candidate development, preclinical testing, and clinical trials, including negative or ambiguous results\plain\cf1\f51\fs20\ql as well as positive findings, are submitted to the FDA as part of a BLA requesting a license to market the product. The BLA\plain\cf1\f51\fs20\ql must contain extensive manufacturing information and detailed information on the composition of the product and proposed\plain\cf1\f51\fs20\ql labeling as well as payment of a user fee.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The FDA has 60\~days after submission of the application to conduct an initial review to determine whether it is sufficient\plain\cf1\f51\fs20\ql to accept for filing based on the agency\u8217?s threshold determination that it is sufficiently complete to permit substantive\plain\cf1\f51\fs20\ql review. Once the submission has been accepted for filing, the FDA begins an in-depth review of the application. Under the goals\plain\cf1\f51\fs20\ql and policies agreed to by the FDA under the Prescription Drug User Fee Act, or the PDUFA, the FDA has ten months in which\plain\cf1\f51\fs20\ql to complete its initial review of a standard application and respond to the applicant, and six months for a priority review of the\plain\cf1\f51\fs20\ql application. The FDA does not always meet its PDUFA goal dates for standard and priority BLAs. The review process may often\plain\cf1\f51\fs20\ql be significantly extended by FDA requests for additional information or clarification. The review process and the PDUFA goal\plain\cf1\f51\fs20\ql date may be extended by three months if the FDA requests or if the applicant otherwise provides through the submission of a\plain\cf1\f51\fs20\ql major amendment additional information or clarification regarding information already provided in the submission within the last\plain\cf1\f51\fs20\ql three months before the PDUFA goal date.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Under the PHSA, the FDA may approve a BLA if it determines that the product is safe, pure, and potent and the facility\plain\cf1\f51\fs20\ql where the product will be manufactured meets standards designed to ensure that it continues to be safe, pure, and potent.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql On the basis of the FDA\u8217?s evaluation of the application and accompanying information, including the results of the\plain\cf1\f51\fs20\ql inspection of the manufacturing facilities and any FDA audits of nonclinical study and clinical trial sites to assure compliance\plain\cf1\f51\fs20\ql with GLPs and GCPs, respectively, the FDA may issue an approval letter or a complete response letter. An approval letter\plain\cf1\f51\fs20\ql authorizes commercial marketing of the product with specific prescribing information for specific indications. If the application is\plain\cf1\f51\fs20\ql not approved, the FDA will issue a complete response letter, which will contain the conditions that must be met in order to\plain\cf1\f51\fs20\ql secure final approval of the application, and when possible will outline recommended actions the sponsor might take to obtain\plain\cf1\f51\fs20\ql approval of the application. Sponsors that receive a complete response letter may submit to the FDA information that represents a\plain\cf1\f51\fs20\ql complete response to the issues identified by the FDA. Such resubmissions are classified under PDUFA as either Class\~1 or\plain\cf1\f51\fs20\ql Class\~2. The classification of a resubmission is based on the information submitted by an applicant in response to an action letter.\plain\cf1\f51\fs20\ql Under the goals and policies agreed to by the FDA under PDUFA, the FDA has two months to review a Class\~1 resubmission\plain\cf1\f51\fs20\ql and six months to review a Class\~2 resubmission. The FDA will not approve an application until issues identified in the complete\plain\cf1\f51\fs20\ql response letter have been addressed.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The FDA may also refer the application to an advisory committee for review, evaluation, and recommendation as to\plain\cf1\f51\fs20\ql whether the application should be approved. In particular, the FDA may refer applications for novel biologic products or biologic\plain\cf1\f51\fs20\ql products that present difficult questions of safety or efficacy to an advisory committee. Typically, an advisory committee is a\plain\cf1\f51\fs20\ql panel of independent experts, including clinicians and other scientific experts, that reviews, evaluates, and provides a\plain\cf1\f51\fs20\ql recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the\plain\cf1\f51\fs20\ql recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.\par\pard\plain\sb264\cf1\f51\fs20\qc 28\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql If the FDA approves a new product, it may limit the approved indications for use of the product. It may also require that\plain\cf1\f51\fs20\ql contraindications, warnings or precautions be included in the product labeling. In addition, the FDA may call for post-approval\plain\cf1\f51\fs20\ql studies, including Phase\~4 clinical trials, to further assess the product\u8217?s safety after approval. The agency may also require\plain\cf1\f51\fs20\ql testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including\plain\cf1\f51\fs20\ql distribution restrictions or other risk management mechanisms, including REMS, to help ensure that the benefits of the product\plain\cf1\f51\fs20\ql outweigh the potential risks. REMS can include medication guides, communication plans for healthcare professionals, and\plain\cf1\f51\fs20\ql elements to assure safe use, or ETASU. ETASU can include, but are not limited to, specific or special training or certification for\plain\cf1\f51\fs20\ql prescribing or dispensing, dispensing only under certain circumstances, special monitoring, and the use of patent registries. The\plain\cf1\f51\fs20\ql FDA may prevent or limit further marketing of a product based on the results of post-market studies or surveillance programs.\plain\cf1\f51\fs20\ql After approval, many types of changes to the approved product, such as adding new indications, certain manufacturing changes\plain\cf1\f51\fs20\ql and additional labeling claims, are subject to further testing requirements and FDA review and approval.\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Fast Track, Breakthrough Therapy and Priority Review Designations\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql The FDA is authorized to designate certain products for expedited review if they are intended to address an unmet medical\plain\cf1\f51\fs20\ql need in the treatment of a serious or life-threatening disease or condition. These programs are referred to as fast track\plain\cf1\f51\fs20\ql designation, breakthrough therapy designation, and priority review designation.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Specifically, the FDA may designate a product for fast track review if it is intended, whether alone or in combination with\plain\cf1\f51\fs20\ql one or more other products, for the treatment of a serious or life-threatening disease or condition, and it demonstrates the\plain\cf1\f51\fs20\ql potential to address unmet medical needs for such a disease or condition. For fast track products, sponsors may have greater\plain\cf1\f51\fs20\ql interactions with the FDA and the FDA may initiate review of sections of a fast track product\u8217?s application before the\plain\cf1\f51\fs20\ql application is complete. This rolling review may be available if the FDA determines, after preliminary evaluation of clinical data\plain\cf1\f51\fs20\ql submitted by the sponsor, that a fast track product may be effective. The sponsor must also provide, and the FDA must approve,\plain\cf1\f51\fs20\ql a schedule for the submission of the remaining information and the sponsor must pay applicable user fees. However, the\plain\cf1\f51\fs20\ql FDA\u8217?s time period goal for reviewing a fast track application does not begin until the last section of the application is\plain\cf1\f51\fs20\ql submitted. In addition, the fast track designation may be withdrawn by the FDA if the FDA believes that the designation is no\plain\cf1\f51\fs20\ql longer supported by data emerging in the clinical trial process, or if the designated drug development program is no longer being\plain\cf1\f51\fs20\ql pursued.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Second, in 2012, Congress enacted the Food and Drug Administration Safety and Innovation Act, or FDASIA. This law\plain\cf1\f51\fs20\ql established a new regulatory scheme allowing for expedited review of products designated as \u8220?breakthrough\plain\cf1\f51\fs20\ql therapies.\u8221? A product may be designated as a breakthrough therapy if it is intended, either alone or in combination with\plain\cf1\f51\fs20\ql one or more other products, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates\plain\cf1\f51\fs20\ql that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints,\plain\cf1\f51\fs20\ql such as substantial treatment effects observed early in clinical development. The FDA may take certain actions with respect to\plain\cf1\f51\fs20\ql breakthrough therapies, including holding meetings with the sponsor throughout the development process; providing timely advice\plain\cf1\f51\fs20\ql to the product sponsor regarding development and approval; involving more senior staff in the review process; assigning a\plain\cf1\f51\fs20\ql cross-disciplinary project lead for the review team; and taking other steps to design the clinical trials in an efficient manner.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Third, the FDA may designate a product for priority review if it is a product that treats a serious condition and, if\plain\cf1\f51\fs20\ql approved, would provide a significant improvement in safety or effectiveness. The FDA determines, on a case-by-case basis,\plain\cf1\f51\fs20\ql whether the proposed product represents a significant improvement when compared with other available therapies. Significant\plain\cf1\f51\fs20\ql improvement may be illustrated by evidence of increased effectiveness in the treatment of a condition, elimination or substantial\plain\cf1\f51\fs20\ql reduction of a treatment-limiting adverse reaction, documented enhancement of patient compliance that may lead to improvement\plain\cf1\f51\fs20\ql in serious outcomes, and evidence of safety and effectiveness in a new subpopulation. A priority designation is intended to direct\plain\cf1\f51\fs20\ql overall attention and resources to the evaluation of such applications, and to shorten the FDA\u8217?s goal for taking action on a\plain\cf1\f51\fs20\ql marketing application from ten months to six months.\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Accelerated Approval Pathway\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql The FDA may grant accelerated approval to a product for a serious or life-threatening condition that provides meaningful\plain\cf1\f51\fs20\ql therapeutic advantage to patients over existing treatments based upon a determination that the product has an effect on a\plain\cf1\f51\fs20\ql surrogate endpoint that is reasonably likely to predict clinical benefit. The FDA may also grant accelerated approval for such a\plain\cf1\f51\fs20\ql condition when the product has an effect on an intermediate clinical endpoint that can be measured earlier than an effect on\plain\cf1\f51\fs20\ql irreversible morbidity or mortality, or IMM, and that is reasonably likely to predict an effect on IMM or other clinical benefit,\plain\cf1\f51\fs20\ql taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.\plain\cf1\f51\fs20\ql Products granted accelerated approval must meet the same statutory standards for safety and effectiveness as those granted\plain\cf1\f51\fs20\ql traditional approval.\par\pard\plain\sb264\cf1\f51\fs20\qc 29\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql For the purposes of accelerated approval, a surrogate endpoint is a marker, such as a laboratory measurement, radiographic\plain\cf1\f51\fs20\ql image, physical sign, or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit.\plain\cf1\f51\fs20\ql Surrogate endpoints can often be measured more easily or more rapidly than clinical endpoints. An intermediate clinical endpoint\plain\cf1\f51\fs20\ql is a measurement of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a product, such as\plain\cf1\f51\fs20\ql an effect on IMM. The FDA has limited experience with accelerated approvals based on intermediate clinical endpoints but has\plain\cf1\f51\fs20\ql indicated that such endpoints generally could support accelerated approval where a study demonstrates a relatively short-term\plain\cf1\f51\fs20\ql clinical benefit in a chronic disease setting in which assessing durability of the clinical benefit is essential for traditional approval,\plain\cf1\f51\fs20\ql but the short-term benefit is considered reasonably likely to predict long-term benefit.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The accelerated approval pathway is most often used in settings in which the course of a disease is long and an extended\plain\cf1\f51\fs20\ql period of time is required to measure the intended clinical benefit of a product, even if the effect on the surrogate or intermediate\plain\cf1\f51\fs20\ql clinical endpoint occurs rapidly. Thus, accelerated approval has been used extensively in the development and approval of\plain\cf1\f51\fs20\ql products for treatment of a variety of cancers in which the goal of therapy is generally to improve survival or decrease morbidity\plain\cf1\f51\fs20\ql and the duration of the typical disease course requires lengthy and sometimes large trials to demonstrate a clinical or survival\plain\cf1\f51\fs20\ql benefit.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The accelerated approval pathway is usually contingent on a sponsor\u8217?s agreement to conduct, in a diligent manner,\plain\cf1\f51\fs20\ql additional post-approval confirmatory studies to verify and describe the product\u8217?s clinical benefit. As a result, a product\plain\cf1\f51\fs20\ql candidate approved on this basis is subject to rigorous post-marketing compliance requirements, including the completion of\plain\cf1\f51\fs20\ql Phase\~4 or post-approval clinical trials to confirm the effect on the clinical endpoint. Failure to conduct required post-approval\plain\cf1\f51\fs20\ql studies, or confirm a clinical benefit during post-marketing studies, would allow the FDA to withdraw the product from the\plain\cf1\f51\fs20\ql market on an expedited basis. All promotional materials for product candidates approved under accelerated regulations are subject\plain\cf1\f51\fs20\ql to prior review by the FDA.\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Post-Approval Regulation\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql If regulatory approval for marketing of a product or new indication for an existing product is obtained, the sponsor will be\plain\cf1\f51\fs20\ql required to comply with all regular post-approval regulatory requirements as well as any post-approval requirements that the\plain\cf1\f51\fs20\ql FDA has imposed as part of the approval process. The sponsor will be required to report certain adverse reactions and production\plain\cf1\f51\fs20\ql problems to the FDA, provide updated safety and efficacy information and comply with requirements concerning advertising and\plain\cf1\f51\fs20\ql promotional labeling requirements. Manufacturers and certain of their subcontractors are required to register their establishments\plain\cf1\f51\fs20\ql with the FDA and certain state agencies and are subject to periodic unannounced inspections by the FDA and certain state\plain\cf1\f51\fs20\ql agencies for compliance with ongoing regulatory requirements, including cGMP regulations, which impose certain procedural and\plain\cf1\f51\fs20\ql documentation requirements upon manufacturers. Accordingly, the sponsor and its third-party manufacturers must continue to\plain\cf1\f51\fs20\ql expend time, money, and effort in the areas of production and quality control to maintain compliance with cGMP regulations and\plain\cf1\f51\fs20\ql other regulatory requirements.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql A product may also be subject to official lot release, meaning that the manufacturer is required to perform certain tests on\plain\cf1\f51\fs20\ql each lot of the product before it is released for distribution. If the product is subject to official lot release, the manufacturer must\plain\cf1\f51\fs20\ql submit samples of each lot, together with a release protocol showing a summary of the history of manufacture of the lot and the\plain\cf1\f51\fs20\ql results of all of the manufacturer\u8217?s tests performed on the lot, to the FDA. The FDA may in addition perform certain\plain\cf1\f51\fs20\ql confirmatory tests on lots of some products before releasing the lots for distribution. Finally, the FDA will conduct laboratory\plain\cf1\f51\fs20\ql research related to the safety, purity, potency, and effectiveness of pharmaceutical products.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Once an approval is granted, the FDA may withdraw the approval if compliance with regulatory requirements is not\plain\cf1\f51\fs20\ql maintained or if problems occur after the product reaches the market. Later discovery of previously unknown problems with a\plain\cf1\f51\fs20\ql product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply\plain\cf1\f51\fs20\ql with regulatory requirements, may result in revisions to the approved labeling to add new safety information; imposition of\plain\cf1\f51\fs20\ql post-market studies or clinical trials to assess new safety risks; or imposition of distribution or other restrictions under a REMS\plain\cf1\f51\fs20\ql program. Other potential consequences include, among other things:
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market\plain\intbl\cf1\f51\fs20\ql or product recalls;\cell{
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\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql fines, untitled or warning letters or holds on post-approval clinical trials;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql refusal of the FDA to approve pending applications or supplements to approved applications, or suspension or\plain\intbl\cf1\f51\fs20\ql revocation of product license approvals;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql product seizure or detention, or refusal to permit the import or export of products; or\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql injunctions or the imposition of civil or criminal penalties.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}\pard\plain\sb264\cf1\f51\fs20\qc 30\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The FDA strictly regulates marketing, labeling, advertising and promotion of licensed and approved products that are placed\plain\cf1\f51\fs20\ql on the market. Pharmaceutical products may be promoted only for the approved indications and in accordance with the provisions\plain\cf1\f51\fs20\ql of the approved label. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of\plain\cf1\f51\fs20\ql off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability.\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Orphan Drug Designation\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Orphan drug designation in the United States is designed to encourage sponsors to develop products intended for rare\plain\cf1\f51\fs20\ql diseases or conditions. In the United States, a rare disease or condition is statutorily defined as a condition that affects fewer than\plain\cf1\f51\fs20\ql 200,000 individuals in the United States or that affects more than 200,000 individuals in the United States and for which there is\plain\cf1\f51\fs20\ql no reasonable expectation that the cost of developing and making available the biologic for the disease or condition will be\plain\cf1\f51\fs20\ql recovered from sales of the product in the United States.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Orphan drug designation qualifies a company for tax credits and market exclusivity for seven years following the date of\plain\cf1\f51\fs20\ql the product\u8217?s marketing approval if granted by the FDA. An application for designation as an orphan product can be made\plain\cf1\f51\fs20\ql any time prior to the filing of an application for approval to market the product. A product becomes an orphan when it receives\plain\cf1\f51\fs20\ql orphan drug designation from the Office of Orphan Products Development, or OOPD, at the FDA based on acceptable\plain\cf1\f51\fs20\ql confidential requests made under the regulatory provisions. The product must then go through the review and approval process\plain\cf1\f51\fs20\ql for commercial distribution like any other product.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql A sponsor may request orphan drug designation of a previously unapproved product or new orphan indication for an\plain\cf1\f51\fs20\ql already marketed product. In addition, a sponsor of a product that is otherwise the same product as an already approved orphan\plain\cf1\f51\fs20\ql drug may seek and obtain orphan drug designation for the subsequent product for the same rare disease or condition if it can\plain\cf1\f51\fs20\ql present a plausible hypothesis that its product may be clinically superior to the first drug. More than one sponsor may receive\plain\cf1\f51\fs20\ql orphan drug designation for the same product for the same rare disease or condition, but each sponsor seeking orphan drug\plain\cf1\f51\fs20\ql designation must file\~a complete request for designation.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The period of exclusivity begins on the date that the marketing application is approved by the FDA and applies only to the\plain\cf1\f51\fs20\ql indication for which the product has been designated. The FDA may approve a second application for the same product for a\plain\cf1\f51\fs20\ql different use or a second application for a clinically superior version of the product for the same use. The FDA cannot, however,\plain\cf1\f51\fs20\ql approve the same product made by another manufacturer for the same indication during the market exclusivity period unless it\plain\cf1\f51\fs20\ql has the consent of the sponsor or the sponsor is unable to provide sufficient quantities.\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Pediatric Studies and Exclusivity\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Under the Pediatric Research Equity Act of 2003, a BLA or supplement thereto must contain data that are adequate to\plain\cf1\f51\fs20\ql assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations, and to\plain\cf1\f51\fs20\ql support dosing and administration for each pediatric subpopulation for which the product is safe and effective. Sponsors must\plain\cf1\f51\fs20\ql also submit pediatric study plans prior to the assessment data. Those plans must contain an outline of the proposed pediatric\plain\cf1\f51\fs20\ql study or studies the applicant plans to conduct, including study objectives and design, any deferral or waiver requests, and other\plain\cf1\f51\fs20\ql information required by regulation. The applicant, the FDA, and the FDA\u8217?s internal review committee must then review\plain\cf1\f51\fs20\ql the information submitted, consult with each other, and agree upon a final plan. The FDA or the applicant may request an\plain\cf1\f51\fs20\ql amendment to the plan at any time.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all\plain\cf1\f51\fs20\ql pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.\plain\cf1\f51\fs20\ql Additional requirements and procedures relating to deferral requests and requests for extension of deferrals are contained in\plain\cf1\f51\fs20\ql FDASIA. Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan\plain\cf1\f51\fs20\ql designation.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Pediatric exclusivity is another type of non-patent marketing exclusivity in the United States and, if granted, provides for\plain\cf1\f51\fs20\ql the attachment of an additional six months of marketing protection to the term of any existing regulatory exclusivity, including\plain\cf1\f51\fs20\ql the non-patent and orphan exclusivity. This six-month exclusivity may be granted if a BLA sponsor submits pediatric data that\plain\cf1\f51\fs20\ql fairly respond to a written request from the FDA for such data. The data do not need to show the product to be effective in the\plain\cf1\f51\fs20\ql pediatric population studied; rather, if the clinical trial is deemed to fairly respond to the FDA\u8217?s request, the additional\plain\cf1\f51\fs20\ql protection is granted. If reports of requested pediatric studies are submitted to and accepted by the FDA within the statutory time\plain\cf1\f51\fs20\ql limits, whatever statutory or regulatory periods of exclusivity or patent protection cover the product are extended by six months.\plain\cf1\f51\fs20\ql This is not a patent term extension, but it effectively extends the regulatory period during which the FDA cannot approve another\plain\cf1\f51\fs20\ql application.\par\pard\plain\sb264\cf1\f51\fs20\qc 31\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Biosimilars and Exclusivity\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql The Patient Protection and Affordable Care Act, which was signed into law in March 2010, included a subtitle called the\plain\cf1\f51\fs20\ql Biologics Price Competition and Innovation Act of 2009 or BPCIA. The BPCIA established a regulatory scheme authorizing the\plain\cf1\f51\fs20\ql FDA to approve biosimilars and interchangeable biosimilars. To date, four biosimilar products have been approved by the FDA\plain\cf1\f51\fs20\ql for use in the United States. No interchangeable biosimilars, however, have been approved. The FDA has issued several guidance\plain\cf1\f51\fs20\ql documents outlining an approach to review and approval of biosimilars. Additional guidances are expected to be finalized by the\plain\cf1\f51\fs20\ql FDA in the near term.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Under the BPCIA, a manufacturer may submit an application for licensure of a biologic product that is \u8220?biosimilar\plain\cf1\f51\fs20\ql to\u8221? or \u8220?interchangeable with\u8221? a previously approved biological product or \u8220?reference product.\u8221?\plain\cf1\f51\fs20\ql In order for the FDA to approve a biosimilar product, it must find that there are no clinically meaningful differences between the\plain\cf1\f51\fs20\ql reference product and proposed biosimilar product in terms of safety, purity, and potency. For the FDA to approve a biosimilar\plain\cf1\f51\fs20\ql product as interchangeable with a reference product, the agency must find that the biosimilar product can be expected to produce\plain\cf1\f51\fs20\ql the same clinical results as the reference product, and (for products administered multiple times) that the biologic and the\plain\cf1\f51\fs20\ql reference biologic may be switched after one has been previously administered without increasing safety risks or risks of\plain\cf1\f51\fs20\ql diminished efficacy relative to exclusive use of the reference biologic.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Under the BPCIA, an application for a biosimilar product may not be submitted to the FDA until four years following the\plain\cf1\f51\fs20\ql date of approval of the reference product. The FDA may not approve a biosimilar product until 12\~years from the date on which\plain\cf1\f51\fs20\ql the reference product was approved. Even if a product is considered to be a reference product eligible for exclusivity, another\plain\cf1\f51\fs20\ql company could market a competing version of that product if the FDA approves a full BLA for such product containing the\plain\cf1\f51\fs20\ql sponsor\u8217?s own preclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity,\plain\cf1\f51\fs20\ql and potency of their product. The BPCIA also created certain exclusivity periods for biosimilars approved as interchangeable\plain\cf1\f51\fs20\ql products. At this juncture, it is unclear whether products deemed \u8220?interchangeable\u8221? by the FDA will, in fact, be\plain\cf1\f51\fs20\ql readily substituted by pharmacies, which are governed by state pharmacy law.\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Patent Term Restoration and Extension\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql A patent claiming a new biologic product may be eligible for a limited patent term extension under the Hatch-Waxman\plain\cf1\f51\fs20\ql Act, which permits a patent restoration of up to five years for patent term lost during product development and FDA regulatory\plain\cf1\f51\fs20\ql review. The restoration period granted on a patent covering a product is typically one-half the time between the effective date of\plain\cf1\f51\fs20\ql an IND and the submission date of a marketing application, plus the time between the submission date of the marketing\plain\cf1\f51\fs20\ql application and the ultimate approval date, less any time the applicant failed to act with due diligence. Patent term restoration\plain\cf1\f51\fs20\ql cannot be used to extend the remaining term of a patent past a total of 14\~years from the product\u8217?s approval date. Only\plain\cf1\f51\fs20\ql one patent applicable to an approved product is eligible for the extension, and the application for the extension must be submitted\plain\cf1\f51\fs20\ql prior to the expiration of the patent in question. A patent that covers multiple products for which approval is sought can only be\plain\cf1\f51\fs20\ql extended in connection with one of the approvals. The USPTO\~reviews and approves the application for any patent term\plain\cf1\f51\fs20\ql extension or restoration in consultation with the FDA.\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql Regulation And Procedures Governing Approval Of Medicinal Products In The European Union\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql In order to market any product outside of the United States, a company must also comply with numerous and varying\plain\cf1\f51\fs20\ql regulatory requirements of other countries and jurisdictions regarding quality, safety and efficacy and governing, among other\plain\cf1\f51\fs20\ql things, clinical trials, marketing authorization, commercial sales and distribution of products. Whether or not it obtains FDA\plain\cf1\f51\fs20\ql approval for a product, an applicant will need to obtain the necessary approvals by the comparable health regulatory authorities\plain\cf1\f51\fs20\ql before it can commence clinical trials or marketing of the product in those countries or jurisdictions. Specifically, the process\plain\cf1\f51\fs20\ql governing approval of medicinal products in the European Union, or EU, generally follows the same lines as in the United States.\plain\cf1\f51\fs20\ql It entails satisfactory completion of preclinical studies and adequate and well-controlled clinical trials to establish the safety and\plain\cf1\f51\fs20\ql efficacy of the product for each proposed indication. It also requires the submission to the European Medicines Agency, or EMA,\plain\cf1\f51\fs20\ql or the relevant competent authorities of a marketing authorization application, or MAA, and granting of a marketing authorization\plain\cf1\f51\fs20\ql by the EMA or these authorities before the product can be marketed and sold in the EU.\par\pard\plain\sb264\cf1\f51\fs20\qc 32\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Clinical Trial Approval\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Pursuant to the currently applicable Clinical Trials Directive 2001/20/EC and the Commission Directive\~2005/28/EC on\plain\cf1\f51\fs20\ql GCP, a system for the approval of clinical trials in the EU has been implemented through national legislation of the member\plain\cf1\f51\fs20\ql states. Under this system, an applicant must obtain approval from the competent national authority of an EU member state in\plain\cf1\f51\fs20\ql which the clinical trial is to be conducted, or in multiple member states if the clinical trial is to be conducted in a number of\plain\cf1\f51\fs20\ql member states. Furthermore, the applicant may only start a clinical trial at a specific study site after the ethics committee has\plain\cf1\f51\fs20\ql issued a favorable opinion. The CTA must be accompanied by an investigational medicinal product dossier with supporting\plain\cf1\f51\fs20\ql information prescribed by Directive 2001/20/EC and Commission Directive 2005/28/EC and corresponding national laws of the\plain\cf1\f51\fs20\ql member states and further detailed in applicable guidance documents.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In April 2014, the EU adopted a new Clinical Trials Regulation (EU)\~No\~536/2014, which is set to replace the current\plain\cf1\f51\fs20\ql Clinical Trials Directive 2001/20/EC. The new Clinical Trials Regulation (EU)\~No\~536/2014 will become applicable no earlier\plain\cf1\f51\fs20\ql than May\~28, 2016. It will overhaul the current system of approvals for clinical trials in the EU. Specifically, the new legislation,\plain\cf1\f51\fs20\ql which will be directly applicable in all member states, aims at simplifying and streamlining the approval of clinical trials in the\plain\cf1\f51\fs20\ql EU. For instance, the new Clinical Trials Regulation provides for a streamlined application procedure via a single-entry point\plain\cf1\f51\fs20\ql and strictly defined deadlines for the assessment of clinical trial applications.\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Marketing Authorization\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql To obtain a marketing authorization for a product under the EU regulatory system, an applicant must submit an MAA,\plain\cf1\f51\fs20\ql either under a centralized procedure administered by the European Medicines Agency, or EMA, or one of the procedures\plain\cf1\f51\fs20\ql administered by competent authorities in EU\~Member States (decentralized procedure, national procedure, or mutual recognition\plain\cf1\f51\fs20\ql procedure). A marketing authorization may be granted only to an applicant established in the EU. Regulation (EC) No 1901/2006\plain\cf1\f51\fs20\ql provides that prior to obtaining a marketing authorization in the EU, an applicant must demonstrate compliance with all measures\plain\cf1\f51\fs20\ql included in an EMA-approved Pediatric Investigation Plan, or PIP, covering all subsets of the pediatric population, unless the\plain\cf1\f51\fs20\ql EMA has granted a product-specific waiver, class waiver, or a deferral for one or more of the measures included in the PIP.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The centralized procedure provides for the grant of a single marketing authorization by the European Commission that is\plain\cf1\f51\fs20\ql valid for all EU member states. Pursuant to Regulation (EC) No.\~726/2004, the centralized procedure is compulsory for specific\plain\cf1\f51\fs20\ql products, including for medicines produced by certain biotechnological processes, products designated as orphan medicinal\plain\cf1\f51\fs20\ql products, advanced therapy products and products with a new active substance indicated for the treatment of certain diseases,\plain\cf1\f51\fs20\ql including products for the treatment of cancer. For products that are highly innovative or for which a centralized process is in the\plain\cf1\f51\fs20\ql interest of patients, the centralized procedure may be optional.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Specifically, the grant of marketing authorization in the European Union for products containing viable human tissues or\plain\cf1\f51\fs20\ql cells such as gene therapy medicinal products is governed by Regulation\~(EC) No 1394/2007 on advanced therapy medicinal\plain\cf1\f51\fs20\ql products, read in combination with Directive\~2001/83/EC of the European Parliament and of the Council, commonly known as\plain\cf1\f51\fs20\ql the Community code on medicinal products. Regulation\~(EC) No 1394/2007 lays down specific rules concerning the\plain\cf1\f51\fs20\ql authorization, supervision, and pharmacovigilance of gene therapy medicinal products, somatic cell therapy medicinal products,\plain\cf1\f51\fs20\ql and tissue engineered products. Manufacturers of advanced therapy medicinal products must demonstrate the quality, safety, and\plain\cf1\f51\fs20\ql efficacy of their products to EMA which provides an opinion regarding the application for marketing authorization. The European\plain\cf1\f51\fs20\ql Commission grants or refuses marketing authorization in light of the opinion delivered by EMA.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Under the centralized procedure, the Committee for Medicinal Products for Human Use, or the CHMP, established at the\plain\cf1\f51\fs20\ql EMA is responsible for conducting an initial assessment of a product. Under the centralized procedure in the European Union,\plain\cf1\f51\fs20\ql the maximum timeframe for the evaluation of an MAA is 210\~days, excluding clock stops when additional information or written\plain\cf1\f51\fs20\ql or oral explanation is to be provided by the applicant in response to questions of the CHMP. Accelerated evaluation may be\plain\cf1\f51\fs20\ql granted by the CHMP in exceptional cases, when a medicinal product is of major interest from the point of view of public health\plain\cf1\f51\fs20\ql and, in particular, from the viewpoint of therapeutic innovation. If the CHMP accepts such a request, the time limit of 210\~days\plain\cf1\f51\fs20\ql will be reduced to 150\~days, but it is possible that the CHMP may revert to the standard time limit for the centralized procedure\plain\cf1\f51\fs20\ql if it determines that it is no longer appropriate to conduct an accelerated assessment.\par\pard\plain\sb264\cf1\f51\fs20\qc 33\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Regulatory Data Protection in the European Union\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql In the European Union, new chemical entities approved on the basis of a complete independent data package qualify for\plain\cf1\f51\fs20\ql eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity pursuant to\plain\cf1\f51\fs20\ql Regulation (EC) No 726/2004, as amended, and Directive\~2001/83/EC, as amended. Data exclusivity prevents regulatory\plain\cf1\f51\fs20\ql authorities in the European Union from referencing the innovator\u8217?s data to assess a generic (abbreviated) application for a\plain\cf1\f51\fs20\ql period of eight years. During the additional two-year period of market exclusivity, a generic marketing authorization application\plain\cf1\f51\fs20\ql can be submitted, and the innovator\u8217?s data may be referenced, but no generic medicinal product can be marketed until the\plain\cf1\f51\fs20\ql expiration of the market exclusivity. The overall ten-year period will be extended to a maximum of eleven years if, during the\plain\cf1\f51\fs20\ql first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic\plain\cf1\f51\fs20\ql indications which, during the scientific evaluation prior to authorization, is held to bring a significant clinical benefit in\plain\cf1\f51\fs20\ql comparison with existing therapies. Even if a compound is considered to be a new chemical entity so that the innovator gains the\plain\cf1\f51\fs20\ql prescribed period of data exclusivity, another company may market another version of the product if such company obtained\plain\cf1\f51\fs20\ql marketing authorization based on an MAA with a complete independent data package of pharmaceutical tests, preclinical tests\plain\cf1\f51\fs20\ql and clinical trials.\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Periods of Authorization and Renewals\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql A marketing authorization is valid for five years, in principle, and it may be renewed after five years on the basis of a\plain\cf1\f51\fs20\ql reevaluation of the risk-benefit balance by the EMA or by the competent authority of the authorizing member state. To that end,\plain\cf1\f51\fs20\ql the marketing authorization holder must provide the EMA or the competent authority with a consolidated version of the file in\plain\cf1\f51\fs20\ql respect of quality, safety and efficacy, including all variations introduced since the marketing authorization was granted, at least\plain\cf1\f51\fs20\ql nine months before the marketing authorization ceases to be valid. Once renewed, the marketing authorization is valid for an\plain\cf1\f51\fs20\ql unlimited period, unless the European Commission or the competent authority decides, on justified grounds relating to\plain\cf1\f51\fs20\ql pharmacovigilance, to proceed with one additional five-year renewal period. Any authorization that is not followed by the\plain\cf1\f51\fs20\ql placement of the drug on the EU market (in the case of the centralized procedure) or on the market of the authorizing member\plain\cf1\f51\fs20\ql state within three years after authorization ceases to be valid.\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Regulatory Requirements after Marketing Authorization\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Following approval, the holder of the marketing authorization is required to comply with a range of requirements applicable\plain\cf1\f51\fs20\ql to the manufacturing, marketing, promotion and sale of the medicinal product. These include compliance with the EU\u8217?s\plain\cf1\f51\fs20\ql stringent pharmacovigilance or safety reporting rules, pursuant to which post-authorization studies and additional monitoring\plain\cf1\f51\fs20\ql obligations can be imposed. In addition, the manufacturing of authorized products, for which a separate manufacturer\u8217?s\plain\cf1\f51\fs20\ql license is mandatory, must also be conducted in strict compliance with the EMA\u8217?s GMP requirements and comparable\plain\cf1\f51\fs20\ql requirements of other regulatory bodies in the EU, which mandate the methods, facilities, and controls used in manufacturing,\plain\cf1\f51\fs20\ql processing and packing of drugs to assure their safety and identity. Finally, the marketing and promotion of authorized products,\plain\cf1\f51\fs20\ql including advertising directed toward the prescribers of drugs and/or the general public, are strictly regulated in the European\plain\cf1\f51\fs20\ql Union under Directive 2001/83/EC, as amended.\par\pard\plain\li44\sb396\cf1\f51\fs20\i\ql Orphan Drug Designation and Exclusivity\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Regulation (EC) No 141/2000 and Regulation (EC) No\~847/2000 provide that a product can be designated as an orphan\plain\cf1\f51\fs20\ql drug by the European Commission if its sponsor can establish: that the product is intended for the diagnosis, prevention or\plain\cf1\f51\fs20\ql treatment of (i)\~a life-threatening or chronically debilitating condition affecting not more than five in ten thousand persons in the\plain\cf1\f51\fs20\ql EU when the application is made, or (ii)\~a life-threatening, seriously debilitating or serious and chronic condition in the EU and\plain\cf1\f51\fs20\ql that without incentives it is unlikely that the marketing of the drug in the EU would generate sufficient return to justify the\plain\cf1\f51\fs20\ql necessary investment. For either of these conditions, the applicant must demonstrate that there exists no satisfactory method of\plain\cf1\f51\fs20\ql diagnosis, prevention, or treatment of the condition in question that has been authorized in the EU or, if such method exists, the\plain\cf1\f51\fs20\ql drug will be of significant benefit to those affected by that condition.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql An orphan drug designation provides a number of benefits, including fee reductions, regulatory assistance, and the ability to\plain\cf1\f51\fs20\ql apply for a centralized EU marketing authorization. Marketing authorization for an orphan drug leads to a ten-year period of\plain\cf1\f51\fs20\ql market exclusivity. During this market exclusivity period, neither the European Commission nor the member states can accept an\plain\cf1\f51\fs20\ql application or grant a marketing authorization for a \u8220?similar medicinal product.\u8221? A \u8220?similar medicinal\plain\cf1\f51\fs20\ql product\u8221? is defined as a medicinal product containing a similar active substance or substances as contained in an\plain\cf1\f51\fs20\ql authorized orphan medicinal product, and which is intended for the same therapeutic indication. The market exclusivity period for\plain\cf1\f51\fs20\ql the authorized therapeutic indication may, however, be reduced to six years if, at the end of the fifth year, it is established that\plain\cf1\f51\fs20\ql the product no longer meets the criteria for orphan drug designation because, for example, the product is sufficiently profitable\plain\cf1\f51\fs20\ql not to justify market exclusivity.\par\pard\plain\sb264\cf1\f51\fs20\qc 34\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql For other markets in which we might in future seek to obtain marketing approval for the commercialization of products,\plain\cf1\f51\fs20\ql there are other health regulatory regimes for seeking approval, and we would need to ensure ongoing compliance with applicable\plain\cf1\f51\fs20\ql health regulatory procedures and standards, as well as other governing laws and regulations for each applicable jurisdiction.\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql Coverage, Pricing and Reimbursement\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Significant uncertainty exists as to the coverage and reimbursement status of any product candidates for which we may\plain\cf1\f51\fs20\ql seek regulatory approval by the FDA or other government authorities. In the United States and markets in other countries,\plain\cf1\f51\fs20\ql patients who are prescribed treatments for their conditions and providers performing the prescribed services generally rely on\plain\cf1\f51\fs20\ql third-party payors to reimburse all or part of the associated healthcare costs. Patients are unlikely to use any product candidates\plain\cf1\f51\fs20\ql we may develop unless coverage is provided and reimbursement is adequate to cover a significant portion of the cost of such\plain\cf1\f51\fs20\ql product candidates. Even if any product candidates we may develop are approved, sales of such product candidates will depend,\plain\cf1\f51\fs20\ql in part, on the extent to which third-party payors, including government health programs in the United States such as Medicare\plain\cf1\f51\fs20\ql and Medicaid, commercial health insurers, and managed care organizations, provide coverage, and establish adequate\plain\cf1\f51\fs20\ql reimbursement levels for, such product candidates. The process for determining whether a payor will provide coverage for a\plain\cf1\f51\fs20\ql product may be separate from the process for setting the price or reimbursement rate that the payor will pay for the product once\plain\cf1\f51\fs20\ql coverage is approved. Third-party payors are increasingly challenging the prices charged, examining the medical necessity, and\plain\cf1\f51\fs20\ql reviewing the cost-effectiveness of medical products and services and imposing controls to manage costs. Third-party payors\plain\cf1\f51\fs20\ql may limit coverage to specific products on an approved list, also known as a formulary, which might not include all of the\plain\cf1\f51\fs20\ql approved products for a particular indication.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In order to secure coverage and reimbursement for any product that might be approved for sale, a company may need to\plain\cf1\f51\fs20\ql conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity and cost-effectiveness of the product,\plain\cf1\f51\fs20\ql in addition to the costs required to obtain FDA or other comparable marketing approvals. Nonetheless, product candidates may\plain\cf1\f51\fs20\ql not be considered medically necessary or cost effective. A\~decision by a third-party payor not to cover any product candidates\plain\cf1\f51\fs20\ql we may develop could reduce physician utilization of such product candidates once approved and have a material adverse effect\plain\cf1\f51\fs20\ql on our sales, results of operations and financial condition. Additionally, a payor\u8217?s decision to provide coverage for a\plain\cf1\f51\fs20\ql product does not imply that an adequate reimbursement rate will be approved. Further, one payor\u8217?s determination to\plain\cf1\f51\fs20\ql provide coverage for a product does not assure that other payors will also provide coverage and reimbursement for the product,\plain\cf1\f51\fs20\ql and the level of coverage and reimbursement can differ significantly from payor to payor. Third-party reimbursement and\plain\cf1\f51\fs20\ql coverage may not be available to enable us to maintain price levels sufficient to realize an appropriate return on our investment\plain\cf1\f51\fs20\ql in product development.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The containment of healthcare costs also has become a priority of various federal, state and/or local governments, as well\plain\cf1\f51\fs20\ql as other payors, within the U.S. and in other countries globally, and the prices of pharmaceuticals have been a focus in these\plain\cf1\f51\fs20\ql efforts. Governments and other payors have shown significant interest in implementing cost-containment programs, including\plain\cf1\f51\fs20\ql price controls, restrictions on reimbursement, and requirements for substitution of generic products. Adoption of price controls\plain\cf1\f51\fs20\ql and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures,\plain\cf1\f51\fs20\ql could further limit a company\u8217?s revenue generated from the sale of any approved products. Coverage policies and\plain\cf1\f51\fs20\ql third-party reimbursement rates may change at any time. Even if favorable coverage and reimbursement status is attained for one\plain\cf1\f51\fs20\ql or more products for which a company or its collaborators receive marketing approval, less favorable coverage policies and\plain\cf1\f51\fs20\ql reimbursement rates may be implemented in the future.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Outside the United States, ensuring adequate coverage and payment for any product candidates we may develop will face\plain\cf1\f51\fs20\ql challenges. Pricing of prescription pharmaceuticals is subject to governmental control in many countries. Pricing negotiations with\plain\cf1\f51\fs20\ql governmental authorities can extend well beyond the receipt of regulatory marketing approval for a product and may require us to\plain\cf1\f51\fs20\ql conduct a clinical trial that compares the cost effectiveness of any product candidates we may develop to other available\plain\cf1\f51\fs20\ql therapies. The conduct of such a clinical trial could be expensive and result in delays in our commercialization efforts.\par\pard\plain\sb264\cf1\f51\fs20\qc 35\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In the European Union, pricing and reimbursement schemes vary widely from country to country. Some countries provide\plain\cf1\f51\fs20\ql that products may be marketed only after a reimbursement price has been agreed. Some countries may require the completion of\plain\cf1\f51\fs20\ql additional studies that compare the cost-effectiveness of a particular product candidate to currently available therapies (so called\plain\cf1\f51\fs20\ql health technology assessments, or HTAs) in order to obtain reimbursement or pricing approval. For example, the European Union\plain\cf1\f51\fs20\ql provides options for its member states to restrict the range of products for which their national health insurance systems provide\plain\cf1\f51\fs20\ql reimbursement and to control the prices of medicinal products for human use. E.U. member states may approve a specific price\plain\cf1\f51\fs20\ql for a product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the\plain\cf1\f51\fs20\ql product on the market. Other member states allow companies to fix their own prices for products, but monitor and control\plain\cf1\f51\fs20\ql prescription volumes and issue guidance to physicians to limit prescriptions. Recently, many countries in the European Union\plain\cf1\f51\fs20\ql have increased the amount of discounts required on pharmaceuticals and these efforts could continue as countries attempt to\plain\cf1\f51\fs20\ql manage healthcare expenditures, especially in light of the severe fiscal and debt crises experienced by many countries in the\plain\cf1\f51\fs20\ql European Union. The downward pressure on health care costs in general, particularly prescription products, has become intense.\plain\cf1\f51\fs20\ql As a result, increasingly high barriers are being erected to the entry of new products. Political, economic, and regulatory\plain\cf1\f51\fs20\ql developments may further complicate pricing negotiations, and pricing negotiations may continue after reimbursement has been\plain\cf1\f51\fs20\ql obtained. Reference pricing used by various European Union Member States, and parallel trade (arbitrage between low-priced\plain\cf1\f51\fs20\ql and high-priced member states), can further reduce prices. There can be no assurance that any country that has price controls or\plain\cf1\f51\fs20\ql reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of\plain\cf1\f51\fs20\ql our products, if approved in those countries.\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql Healthcare Law and Regulation\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Healthcare providers and third-party payors play a primary role in the recommendation and prescription of pharmaceutical\plain\cf1\f51\fs20\ql products that are granted marketing approval. Arrangements with providers, consultants, third-party payors, and customers are\plain\cf1\f51\fs20\ql subject to broadly applicable fraud and abuse, anti-kickback, false claims laws, reporting of payments to physicians and teaching\plain\cf1\f51\fs20\ql physicians and patient privacy laws and regulations and other healthcare laws and regulations that may constrain our business\plain\cf1\f51\fs20\ql and/or financial arrangements. Restrictions under applicable federal and state healthcare laws and regulations, include the\plain\cf1\f51\fs20\ql following:
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{\trowd\cellx432\cellx1116\cellx10800\trrh1372
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the U.S. federal Anti-Kickback Statute, which prohibits, among other things, persons and entities from knowingly\plain\intbl\cf1\f51\fs20\ql and willfully soliciting, offering, paying, or receiving remuneration, directly or indirectly, in cash or in kind, to\plain\intbl\cf1\f51\fs20\ql induce or reward either the referral of an individual for, or the purchase, order or recommendation of, any good or\plain\intbl\cf1\f51\fs20\ql service, for which payment may be made, in whole or in part, under a federal healthcare program such as Medicare\plain\intbl\cf1\f51\fs20\ql and Medicaid;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh1372\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh2115
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the federal civil and criminal false claims laws, including the civil U.S. False Claims Act, and civil\plain\intbl\cf1\f51\fs20\ql monetary penalties laws, which prohibit individuals or entities from, among other things, knowingly\plain\intbl\cf1\f51\fs20\ql presenting, or causing to be presented, to the federal government, claims for payment that are false,\plain\intbl\cf1\f51\fs20\ql fictitious, or fraudulent or knowingly making, using, or causing to be made or used a false record or\plain\intbl\cf1\f51\fs20\ql statement to avoid, decrease, or conceal an obligation to pay money to the federal government. In\plain\intbl\cf1\f51\fs20\ql addition, the government may assert that a claim including items and services resulting from a violation\plain\intbl\cf1\f51\fs20\ql of the U.S. federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the U.S.\plain\intbl\cf1\f51\fs20\ql False Claims Act;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh2115\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh1125
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the federal false statements statute prohibits knowingly and willfully falsifying, concealing, or covering up a\plain\intbl\cf1\f51\fs20\ql material fact or making any materially false statement in connection with the delivery of or payment for healthcare\plain\intbl\cf1\f51\fs20\ql benefits, items, or services; similar to the federal Anti-Kickback Statute, a person or entity does not need to have\plain\intbl\cf1\f51\fs20\ql actual knowledge of the statute or specific intent to violate it in order to have committed a violation;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh1125\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh1620
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the U.S. federal Health Insurance Portability and Accountability Act, or HIPAA, as amended by the U.S. Health\plain\intbl\cf1\f51\fs20\ql Information Technology for Economic and Clinical Health Act, and their respective implementing regulations,\plain\intbl\cf1\f51\fs20\ql including the Final Omnibus Rule published in January 2013, which impose obligations with respect to safeguarding\plain\intbl\cf1\f51\fs20\ql the privacy, security, and transmission of individually identifiable information that constitutes protected health\plain\intbl\cf1\f51\fs20\ql information, including mandatory contractual terms and restrictions on the use and/or disclosure of such information\plain\intbl\cf1\f51\fs20\ql without proper authorization;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh1620\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh2115
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the federal transparency requirements known as the federal Physician Payments Sunshine Act, under the U.S.\plain\intbl\cf1\f51\fs20\ql Patient Protection and Affordable Care Act, as amended by the U.S. Health Care and Education Reconciliation Act,\plain\intbl\cf1\f51\fs20\ql collectively the Affordable Care Act or ACA, which requires certain manufacturers of drugs, devices, biologics and\plain\intbl\cf1\f51\fs20\ql medical supplies to report annually to the Centers for Medicare\~& Medicaid Services, or CMS, within the U.S.\plain\intbl\cf1\f51\fs20\ql Department of Health and Human Services, information related to payments and other transfers of value made by\plain\intbl\cf1\f51\fs20\ql that entity to physicians and teaching hospitals, and requires certain manufacturers and applicable group purchasing\plain\intbl\cf1\f51\fs20\ql organizations to report ownership and investment interests held by physicians or their immediate family members;\plain\intbl\cf1\f51\fs20\ql and\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh2115\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh878
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql analogous laws and regulations in other national jurisdictions and states, such as state anti-kickback and false\plain\intbl\cf1\f51\fs20\ql claims laws, which may apply to healthcare items or services that are reimbursed by non-governmental third-party\plain\intbl\cf1\f51\fs20\ql payors, including private insurers.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh878\row}}}\pard\plain\sb264\cf1\f51\fs20\qc 36\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Some state and other laws require pharmaceutical companies to comply with the pharmaceutical industry\u8217?s voluntary\plain\cf1\f51\fs20\ql compliance guidelines and the relevant compliance guidance promulgated by the federal government in addition to requiring\plain\cf1\f51\fs20\ql pharmaceutical manufacturers to report information related to payments to physicians and other health care providers or\plain\cf1\f51\fs20\ql marketing expenditures. State and other laws also govern the privacy and security of health information in some circumstances,\plain\cf1\f51\fs20\ql many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance\plain\cf1\f51\fs20\ql efforts.\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql Healthcare Reform\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql A primary trend in the U.S. healthcare industry and elsewhere is cost containment. There have been a number of federal\plain\cf1\f51\fs20\ql and state proposals during the last few years regarding the pricing of pharmaceutical and biopharmaceutical products, limiting\plain\cf1\f51\fs20\ql coverage and reimbursement for drugs and other medical products, government control and other changes to the healthcare\plain\cf1\f51\fs20\ql system in the United States.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql By way of example, the United States and state governments continue to propose and pass legislation designed to reduce\plain\cf1\f51\fs20\ql the cost of healthcare. In March 2010, the United States Congress enacted the ACA, which, among other things, includes changes\plain\cf1\f51\fs20\ql to the coverage and payment for products under government health care programs. Among the provisions of the ACA of\plain\cf1\f51\fs20\ql importance to our potential product candidates are:
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh1125
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql an annual, nondeductible fee on any entity that manufactures or imports specified branded prescription drugs and\plain\intbl\cf1\f51\fs20\ql biologic products, apportioned among these entities according to their market share in certain government healthcare\plain\intbl\cf1\f51\fs20\ql programs, although this fee would not apply to sales of certain products approved exclusively for orphan\plain\intbl\cf1\f51\fs20\ql indications;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh1125\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh878
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid\plain\intbl\cf1\f51\fs20\ql coverage to certain individuals with income at or below 133% of the federal poverty level, thereby potentially\plain\intbl\cf1\f51\fs20\ql increasing a manufacturer\u8217?s Medicaid rebate liability;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh878\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh1125
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql expanded manufacturers\u8217? rebate liability under the Medicaid Drug Rebate Program by increasing the\plain\intbl\cf1\f51\fs20\ql minimum rebate for both branded and generic drugs and revising the definition of \u8220?average manufacturer\plain\intbl\cf1\f51\fs20\ql price,\u8221? or AMP, for calculating and reporting Medicaid drug rebates on outpatient prescription drug prices\plain\intbl\cf1\f51\fs20\ql and extending rebate liability to prescriptions for individuals enrolled in Medicare Advantage plans;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh1125\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program\plain\intbl\cf1\f51\fs20\ql are calculated for products that are inhaled, infused, instilled, implanted or injected;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql expanded the types of entities eligible for the 340B drug discount program;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh878
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql established the Medicare Part\~D coverage gap discount program by requiring manufacturers to provide a 50%\plain\intbl\cf1\f51\fs20\ql point-of-sale-discount off the negotiated price of applicable products to eligible beneficiaries during their coverage\plain\intbl\cf1\f51\fs20\ql gap period as a condition for the manufacturers\u8217? outpatient products to be covered under Medicare Part\~D;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh878\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative\plain\intbl\cf1\f51\fs20\ql clinical effectiveness research, along with funding for such research;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh1372
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the Independent Payment Advisory Board, or IPAB, which has authority to recommend certain changes to the\plain\intbl\cf1\f51\fs20\ql Medicare program to reduce expenditures by the program that could result in reduced payments for prescription\plain\intbl\cf1\f51\fs20\ql products. However, the IPAB\~implementation has been not been clearly defined. The ACA provided that under\plain\intbl\cf1\f51\fs20\ql certain circumstances IPAB\~recommendations will become law unless Congress enacts legislation that will achieve\plain\intbl\cf1\f51\fs20\ql the same or greater Medicare cost savings; and\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh1372\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh1125
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql established the Center for Medicare and Medicaid Innovation within CMS to test innovative payment and service\plain\intbl\cf1\f51\fs20\ql delivery models to lower Medicare and Medicaid spending, potentially including prescription product spending.\plain\intbl\cf1\f51\fs20\ql Funding has been allocated to support the mission of the Center for Medicare and Medicaid Innovation from 2011\plain\intbl\cf1\f51\fs20\ql to 2019.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh1125\row}}}\pard\plain\sb264\fi528\cf1\f51\fs20\ql Other legislative changes have been proposed and adopted in the United States since the ACA was enacted. For example,\plain\cf1\f51\fs20\ql in August 2011, the Budget Control Act of 2011, among other things, created measures for spending reductions by Congress. A\plain\cf1\f51\fs20\ql Joint Select Committee on Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for\plain\cf1\f51\fs20\ql the years 2012 through 2021, was unable to reach required goals, thereby triggering the legislation\u8217?s automatic reduction\plain\cf1\f51\fs20\ql to several government programs. This includes aggregate reductions of Medicare payments to providers of up to 2%\~per fiscal\plain\cf1\f51\fs20\ql year, which went into effect in April 2013 and will remain in effect through 2024 unless additional Congressional action is taken.\plain\cf1\f51\fs20\ql In January 2013, President Obama signed into law the American Taxpayer Relief Act of 2012, which, among other things, further\plain\cf1\f51\fs20\ql reduced Medicare payments to several providers, including hospitals, imaging centers, and cancer treatment centers, and increased\plain\cf1\f51\fs20\ql the statute of limitations period for the government to recover overpayments to providers from three to five years.\par\pard\plain\sb264\cf1\f51\fs20\qc 37\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql On January 20, 2017, United States President Donald Trump signed an Executive Order directing federal agencies with\plain\cf1\f51\fs20\ql authorities and responsibilities under the Affordable Care Act to waive, defer, grant exemptions from, or delay the\plain\cf1\f51\fs20\ql implementation of any provision of the Affordable Care Act that would impose a fiscal burden on states or a cost, fee, tax,\plain\cf1\f51\fs20\ql penalty or regulatory burden on individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical\plain\cf1\f51\fs20\ql devices. Congress could consider subsequent legislation to replace elements of the Affordable Care Act that are repealed. It is\plain\cf1\f51\fs20\ql unclear whether new legislation modifying the Affordable Care Act will be enacted, and, if so, precisely what the new legislation\plain\cf1\f51\fs20\ql will provide, when it will be enacted and what impact it will have on the availability of healthcare and containing or lowering the\plain\cf1\f51\fs20\ql cost of healthcare. We plan to continue to evaluate the effect that the Affordable Care Act and its possible repeal and\plain\cf1\f51\fs20\ql replacement may have on our business.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql There have been, and likely will continue to be, legislative and regulatory proposals at the national level in the U.S. and\plain\cf1\f51\fs20\ql other jurisdictions globally, as well as at some regional, state and/or local levels within the U.S. or other jurisdictions, directed at\plain\cf1\f51\fs20\ql broadening the availability of healthcare and containing or lowering the cost of healthcare. Such reforms could have an adverse\plain\cf1\f51\fs20\ql effect on anticipated revenues from product candidates that we may successfully develop and for which we may obtain marketing\plain\cf1\f51\fs20\ql approval and may affect our overall financial condition and ability to develop product candidates.\par\pard\plain\li44\sb396\cf1\f51\fs20\b\i\ql Additional Regulation\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql In addition to the foregoing, state, and federal laws regarding environmental protection and hazardous substances, including\plain\cf1\f51\fs20\ql the Occupational Safety and Health Act, the Resource Conservation and Recovery Act, and the Toxic Substances Control Act,\plain\cf1\f51\fs20\ql affect our business. These and other laws govern the use, handling, and disposal of various biologic, chemical, and radioactive\plain\cf1\f51\fs20\ql substances used in, and wastes generated by, operations. If our operations result in contamination of the environment or expose\plain\cf1\f51\fs20\ql individuals to hazardous substances, we could be liable for damages and governmental fines. Equivalent laws have been adopted\plain\cf1\f51\fs20\ql in third countries that impose similar obligations.\par\pard\plain\sb396\cf1\f51\fs20\b\ql Employees{\*\bkmkstart _hlk505086155_12116663}{\*\bkmkend _hlk505086155_12116663}\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql As of December 31, 2017 we had 127 full-time employees, 57 of whom held Ph.D. or M.D. degrees, 101 of whom were\plain\cf1\f51\fs20\ql engaged in research and development, and 26 of whom were engaged in business development, finance, information systems,\plain\cf1\f51\fs20\ql facilities, human resources, legal functions, or administrative support. None of our employees is represented by a labor union, and\plain\cf1\f51\fs20\ql none of our employees has entered into a collective bargaining agreement with us. We consider our employee relations to be\plain\cf1\f51\fs20\ql good.\par\pard\plain\sb396\cf1\f51\fs20\b\ql Information Available on the Internet\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql From time to time, we may use our website to distribute material information. Our financial and other material information\plain\cf1\f51\fs20\ql is routinely posted to and accessible on the Investors section of our website, available at www.crisprtx.com. Investors are\plain\cf1\f51\fs20\ql encouraged to review the Investors section of our website because we may post material information on that site that is not\plain\cf1\f51\fs20\ql otherwise disseminated by us. Information that is contained in and can be accessed through our website is not incorporated into,\plain\cf1\f51\fs20\ql and does not form a part of, this Annual Report.\par\pard\plain\sb264\cf1\f51\fs20\qc 38\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart item_1_3_3}{\*\bkmkend item_1_3_3}{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}{\*\bkmkstart item_1a_risk_factors_12116663}{\*\bkmkend item_1a_risk_factors_12116663}\par\pard\plain\cf1\f51\fs20\b\ql Item 1A. Risk Factors.\par\pard\plain\sb132\fi528\cf1\f51\fs20\i\ql This report contains forward-looking statements that involve risks and uncertainties. Our actual results could differ\plain\cf1\f51\fs20\i\ql materially from those discussed in this report. Factors that could cause or contribute to these differences include, but are not\plain\cf1\f51\fs20\i\ql limited to, those discussed below and elsewhere in this report and in any documents incorporated in this report by reference.\par\pard\plain\sb264\fi528\cf1\f51\fs20\i\ql You should carefully consider the following risk factors, together with all other information in this report, including our\plain\cf1\f51\fs20\i\ql financial statements and notes thereto, and in our other filings with the Securities and Exchange Commission. If any of the\plain\cf1\f51\fs20\i\ql following risks, or other risks not presently known to us or that we currently believe to not be significant, develop into actual\plain\cf1\f51\fs20\i\ql events, then our business, financial condition, results of operations or prospects could be materially adversely affected. If that\plain\cf1\f51\fs20\i\ql happens, the market price of our common shares could decline, and shareholders may lose all or part of their investment.\par\pard\plain\sb396\cf1\f51\fs20\b\ql Risks Related to Our Financial Position and Need for Additional Capital\par\pard\plain\sb132\fi528\cf1\f51\fs20\i\ql We Have Incurred Significant Operating Losses Since Our Inception And Anticipate That We Will Incur Continued Losses\plain\cf1\f51\fs20\i\ql For The Foreseeable Future.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We have funded our operations to date through proceeds from our initial public offering, or the IPO, and concurrent private\plain\cf1\f51\fs20\ql placement of our common shares, private placements of our preferred shares and convertible securities and payments received\plain\cf1\f51\fs20\ql from Casebia Therapeutics, LLP pursuant to our joint venture with Bayer HealthCare LLC, or Bayer Healthcare, and our\plain\cf1\f51\fs20\ql Collaboration Agreement and Joint Development and Commercialization Agreement, or JDA, with Vertex Pharmaceuticals,\plain\cf1\f51\fs20\ql Incorporated, or Vertex. Since inception, we have incurred significant operating losses. Our net loss was $68.4 million, $23.2\plain\cf1\f51\fs20\ql million, and $25.8 million for the years ended December 31, 2017, 2016 and 2015, respectively. As of December 31, 2017 and\plain\cf1\f51\fs20\ql 2016, we had an accumulated deficit of $125.4 million and $57.1 million, respectively. We expect to continue to incur significant\plain\cf1\f51\fs20\ql expenses and operating losses over the next several years and for the foreseeable future. Our prior losses, combined with\plain\cf1\f51\fs20\ql expected future losses, have had and will continue to have an adverse effect on our shareholders\u8217? deficit and working\plain\cf1\f51\fs20\ql capital. We anticipate that our expenses will increase substantially if and as we:
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql initiate clinical trials for our lead hemoglobinopathy program, CTX001, targeting beta-thalassemia and sickle cell\plain\intbl\cf1\f51\fs20\ql disease\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql continue our current research programs and our preclinical and clinical development of product candidates;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql seek to identify additional research programs and additional product candidates;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh878
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql conduct Investigational New Drug, or IND, supporting preclinical studies and initiate clinical trials for our most\plain\intbl\cf1\f51\fs20\ql advanced product candidates which are from our hemoglobinopathy program targeting beta-thalassemia and sickle\plain\intbl\cf1\f51\fs20\ql cell disease;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh878\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql initiate preclinical studies and clinical trials for any other product candidates we identify and choose to develop;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql maintain, expand and protect our intellectual property portfolio;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql seek marketing approvals for any of our product candidates that successfully complete clinical trials;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql further develop our gene editing technology;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql hire additional clinical, quality control and scientific personnel;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql add operational, financial and management information systems and personnel, including personnel to support our\plain\intbl\cf1\f51\fs20\ql product candidate development;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql acquire or in-license other technologies;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql ultimately establish a sales, marketing, and distribution infrastructure to commercialize any products for which we\plain\intbl\cf1\f51\fs20\ql may obtain marketing approval; and\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql operate as a public company.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}\pard\plain\sb264\fi528\cf1\f51\fs20\ql As a result, we expect to continue to incur significant and increasing operating losses for the foreseeable future. Because of\plain\cf1\f51\fs20\ql the numerous risks and uncertainties associated with developing gene editing product candidates, we are unable to predict the\plain\cf1\f51\fs20\ql extent of any future losses or when we will become profitable, if at all. Even if we do become profitable, we may not be able to\plain\cf1\f51\fs20\ql sustain or increase our profitability on a quarterly or annual basis.\par\pard\plain\sb264\cf1\f51\fs20\qc 39\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql We Will Need To Raise Substantial Additional Funding, Which Will Dilute Our Shareholders. If We Are Unable To Raise\plain\cf1\f51\fs20\i\ql Capital When Needed, We Would Be Forced To Delay, Reduce Or Eliminate Some Of Our Product Development Programs Or\plain\cf1\f51\fs20\i\ql Commercialization Efforts.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql The development of gene editing product candidates is capital intensive. We expect our expenses to increase in connection\plain\cf1\f51\fs20\ql with our ongoing activities, particularly as we continue the research and development of, initiate preclinical studies and clinical\plain\cf1\f51\fs20\ql trials for and seek marketing approval for our product candidates. In addition, if we obtain marketing approval for any of our\plain\cf1\f51\fs20\ql product candidates, we expect to incur significant commercialization expenses related to product sales, marketing, manufacturing\plain\cf1\f51\fs20\ql and distribution to the extent that such sales, marketing, manufacturing and distribution are not the responsibility of Bayer\plain\cf1\f51\fs20\ql Healthcare or Vertex, or other future collaborators. We may also need to raise additional funds sooner if we choose to pursue\plain\cf1\f51\fs20\ql additional indications or geographies for our product candidates or otherwise expand more rapidly than we presently anticipate. In\plain\cf1\f51\fs20\ql addition, relative to prior years when we were a private company, we expect to incur significant additional costs associated with\plain\cf1\f51\fs20\ql operating as a public company. Accordingly, we will need to obtain substantial additional funding in connection with our\plain\cf1\f51\fs20\ql continuing operations. If we are unable to raise capital when needed or on attractive terms, we would be forced to delay, reduce\plain\cf1\f51\fs20\ql or eliminate certain of our research and development programs or future commercialization efforts.{\*\bkmkstart _hlk507097695_12116663}{\*\bkmkend _hlk507097695_12116663}{\*\bkmkstart _hlk507097744_12116663}{\*\bkmkend _hlk507097744_12116663}{\*\bkmkstart _hlk507097753_12116663}{\*\bkmkend _hlk507097753_12116663}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql As of December 31, 2017 and 2016, we had cash of approximately $239.8 million and $315.5 million, respectively. In\plain\cf1\f51\fs20\ql January 2018, the Company completed an offering of 5,750,000 shares of common, which were sold at a price of $22.75 per\plain\cf1\f51\fs20\ql share. This offering resulted in $122.6 million of net proceeds to the Company. The underwriting discount of $7.8 million and\plain\cf1\f51\fs20\ql other expenses of $0.4 million related to the equity offering were recorded as an offset to additional paid-in capital.\plain\cf1\f51\fs20\ql With our\plain\cf1\f51\fs20\ql cash on hand as of December 31, 2017 and the proceeds from the January 2018 offering, we expect cash and cash equivalents to\plain\cf1\f51\fs20\ql be sufficient to fund its current operating plan through at least the next 24 months.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Our future capital requirements will depend on, and could increase significantly as a result of, many factors, including:
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the scope, progress, results and costs of clinical trials, drug discovery, preclinical development, and laboratory\plain\intbl\cf1\f51\fs20\ql testing for our wholly owned and partnered product candidates;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the scope, prioritization and number of our research and development programs;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the costs, timing and outcome of regulatory review of our product candidates;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the costs of establishing and maintaining a supply chain for the development and manufacture of our product\plain\intbl\cf1\f51\fs20\ql candidates;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the success of our current joint venture with Bayer Healthcare and our collaboration with Vertex;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql our ability to establish and maintain additional collaborations on favorable terms, if at all;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the achievement of milestones or occurrence of other developments that trigger payments under any additional\plain\intbl\cf1\f51\fs20\ql collaboration agreements we obtain;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the extent to which we are obligated to reimburse, or entitled to reimbursement of, clinical trial costs under future\plain\intbl\cf1\f51\fs20\ql collaboration agreements, if any;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the costs of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property\plain\intbl\cf1\f51\fs20\ql rights and defending intellectual property-related claims;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh878
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the costs of fulfilling our obligations under the Consent to Assignments, Licensing and Common Ownership and\plain\intbl\cf1\f51\fs20\ql Invention Management Agreement to reimburse other parties for costs incurred in connection with the prosecution\plain\intbl\cf1\f51\fs20\ql and maintenance of associated patent rights;\~\~\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh878\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the extent to which we acquire or in-license other product candidates and technologies;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the costs of establishing or contracting for manufacturing capabilities if we obtain regulatory approvals to\plain\intbl\cf1\f51\fs20\ql manufacture our product candidates;\cell{
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\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the costs of establishing or contracting for sales and marketing capabilities if we obtain regulatory approvals to\plain\intbl\cf1\f51\fs20\ql market our product candidates; and\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql our ability to establish and maintain healthcare coverage and adequate reimbursement.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\pard\plain\sb264\fi528\cf1\f51\fs20\ql Any additional fundraising efforts may divert our management from their day-to-day activities, which may adversely affect\plain\cf1\f51\fs20\ql our ability to develop and commercialize our product candidates. We cannot guarantee that future financing will be available in\plain\cf1\f51\fs20\ql sufficient amounts or on terms acceptable to us, if at all. Moreover, the terms of any financing may adversely affect the holdings\plain\cf1\f51\fs20\ql or the rights of our shareholders and the issuance of additional securities, whether equity or debt, by us, or the possibility of such\plain\cf1\f51\fs20\ql issuance, may cause the market price of our shares to decline. The sale of additional equity or convertible securities would dilute\plain\cf1\f51\fs20\ql all of our shareholders\par\pard\plain\sb264\cf1\f51\fs20\qc 40\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb264\cf1\f51\fs20\ql and the terms of these securities may include liquidation or other preferences that adversely affect your rights as a shareholder.\plain\cf1\f51\fs20\ql The incurrence of indebtedness would result in increased fixed payment obligations and we may be required to agree to certain\plain\cf1\f51\fs20\ql restrictive covenants, such as limitations on our ability to incur additional debt, limitations on our ability to acquire, sell or\plain\cf1\f51\fs20\ql license intellectual property rights and other operating restrictions that could adversely impact our ability to conduct our business.\plain\cf1\f51\fs20\ql We could also be required to seek funds through arrangements with collaborators or otherwise at an earlier stage than otherwise\plain\cf1\f51\fs20\ql would be desirable and we may be required to relinquish rights to some of our technologies or product candidates or otherwise\plain\cf1\f51\fs20\ql agree to terms unfavorable to us, any of which may have a material adverse effect on our business, operating results and\plain\cf1\f51\fs20\ql prospects.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql If we are unable to obtain funding on a timely basis, we may be required to significantly curtail, delay or discontinue one\plain\cf1\f51\fs20\ql or more of our research or development programs or the commercialization of any product candidate, or be unable to expand our\plain\cf1\f51\fs20\ql operations or otherwise capitalize on our business opportunities, as desired, which could materially affect our business, financial\plain\cf1\f51\fs20\ql condition and results of operations.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql We Have A Limited Operating History, Which May Make It Difficult To Evaluate Our Technology And Product\plain\cf1\f51\fs20\i\ql Development Capabilities And Predict Our Future Performance.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We are early in our development efforts and we have not initiated clinical trials for any of our product candidates. We\plain\cf1\f51\fs20\ql were formed in October 2013, have no products approved for commercial sale and have not generated any revenue from product\plain\cf1\f51\fs20\ql sales. Our ability to generate product revenue or profits, which we do not expect will occur for many years, if ever, will depend\plain\cf1\f51\fs20\ql heavily on the successful development and eventual commercialization of our product candidates, which may never occur. We\plain\cf1\f51\fs20\ql may never be able to develop or commercialize a marketable product.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We have submitted clinical trial applications, or CTAs, in various European jurisdictions for a clinical trial in\plain\cf1\f51\fs20\ql beta-thalassemia for our lead product candidate from our hemoglobinopathy program and intend to file an IND with the United\plain\cf1\f51\fs20\ql Stated Food and Drug Administration, or FDA for our hemoglobinopathy program targeting sickle cell disease in the first half of\plain\cf1\f51\fs20\ql 2018, but have not yet commenced clinical trials for such programs. Each of our other programs requires additional discovery\plain\cf1\f51\fs20\ql research and then preclinical development.\~All of our programs, including our hemoglobinopathy program, require clinical\plain\cf1\f51\fs20\ql development, regulatory approval in multiple jurisdictions, obtaining manufacturing supply, capacity and expertise, building of a\plain\cf1\f51\fs20\ql commercial organization, substantial investment and significant marketing efforts before we generate any revenue from product\plain\cf1\f51\fs20\ql sales. In addition, our product candidates must be approved for marketing by the FDA or certain other health regulatory agencies,\plain\cf1\f51\fs20\ql including the European Medicines Agency, or EMA, before we may commercialize any product.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Our limited operating history, particularly in light of the rapidly evolving gene editing field, may make it difficult to\plain\cf1\f51\fs20\ql evaluate our technology and industry and predict our future performance. Our short history as an operating company makes any\plain\cf1\f51\fs20\ql assessment of our future success or viability subject to significant uncertainty. We will encounter risks and difficulties frequently\plain\cf1\f51\fs20\ql experienced by early stage companies in rapidly evolving fields. If we do not address these risks successfully, our business will\plain\cf1\f51\fs20\ql suffer. Similarly,\~we expect that our financial condition and operating results will fluctuate significantly from quarter to quarter\plain\cf1\f51\fs20\ql and year to year due to a variety of factors, many of which are beyond our control.\~As a result, our shareholders should not rely\plain\cf1\f51\fs20\ql upon the results of any quarterly or annual period as an indicator of future operating performance.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In addition, as an early stage company, we have encountered unforeseen expenses, difficulties, complications, delays and\plain\cf1\f51\fs20\ql other known and unknown circumstances.\~As we advance our product candidates, we will need to transition from a company with\plain\cf1\f51\fs20\ql a research focus to a company capable of supporting clinical development and if successful, commercial activities. We may not\plain\cf1\f51\fs20\ql be successful in such a transition.{\*\bkmkstart _hlk504998706_12116663}{\*\bkmkend _hlk504998706_12116663}\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Our Ability To Use Tax Loss Carryforwards In Switzerland May Be Limited.{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Under Swiss law, we are entitled to carry forward losses we incur for a period of seven years and we can offset future\plain\cf1\f51\fs20\ql profits, if any, against such losses. As of December 31, 2017, we reported tax loss carry forwards from inception through 2017\plain\cf1\f51\fs20\ql for purposes of Swiss federal direct taxes in the aggregate amount of CHF 103.1 million (including the loss incurred in 2017). As\plain\cf1\f51\fs20\ql we have moved our legal seat from the Canton of Basel-Stadt to the Canton of Zug mid of 2017, it will be the Canton of Zug,\plain\cf1\f51\fs20\ql which is in charge for assessing our tax return including our carry forward losses (to be noted that there will be a pro-rata\plain\cf1\f51\fs20\ql allocation between the Canton of Basel-Stadt and Zug for capital tax purposes in 2017). No ruling regarding taxation as a mixed\plain\cf1\f51\fs20\ql company has been filed with the Zug tax authorities; however, based on the practice of the Canton of Zug, we can apply for\plain\cf1\f51\fs20\ql taxation as a mixed company in the tax return as long as the respective law is in force and we fulfill the respective criteria.\plain\cf1\f51\fs20\ql According to the practice of the Canton of Zug and deviating from the tax rules of the Canton of Basel-Stadt a mixed company\plain\cf1\f51\fs20\ql profit allocation is only performed once the company is profit making. Therefore, the tax loss carry forwards at cantonal level are\plain\cf1\f51\fs20\ql the same as at federal level and therefore amount to some CHF 103.1 million in aggregate as of December 31. 2017. It is to be\plain\cf1\f51\fs20\ql noted in this regard that tax losses are only finally assessed by the tax authorities when offset with taxable profit (which will not\plain\cf1\f51\fs20\ql be the case as long we are loss making). If not used, these tax losses will\par\pard\plain\sb264\cf1\f51\fs20\qc 41\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb132\cf1\f51\fs20\ql expire seven years after the year in which they occurred. Due to our limited income, there is a high risk that the tax loss carry\plain\cf1\f51\fs20\ql forwards will expire partly or entirely. For 2017, the tax return has \u8211? in accordance with Swiss tax law \u8211? not yet\plain\cf1\f51\fs20\ql been filed. Therefore, for 2017 the loss carried forward will only be claimed with filing of the tax return for the tax year 2017.\par\pard\plain\sb396\cf1\f51\fs20\b\ql Risks Related to Our Business, Technology and Industry\par\pard\plain\sb132\fi528\cf1\f51\fs20\i\ql We Are Early In Our Development Efforts And We Have Not Initiated Clinical Trials For Any Of Our Product Candidates.\plain\cf1\f51\fs20\i\ql It Will Be Many Years Before We Or Our Collaborators Commercialize A Product Candidate, If Ever. If We Are Unable To\plain\cf1\f51\fs20\i\ql Advance Our Product Candidates To Clinical Development, Obtain Regulatory Approval And Ultimately Commercialize Our\plain\cf1\f51\fs20\i\ql Product Candidates, Or Experience Significant Delays In Doing So, Our Business Will Be Materially Harmed.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We are early in our development efforts and have focused our research and development efforts to date CRISPR/Cas9, gene\plain\cf1\f51\fs20\ql editing technology, identifying our initial targeted disease indications and our initial product candidates. Our future success\plain\cf1\f51\fs20\ql depends heavily on the successful development of our CRISPR/Cas9 gene editing product candidates including our most\plain\cf1\f51\fs20\ql advanced product candidate, CTX001, which targets beta-thalassemia and sickle cell disease. We have invested substantially all\plain\cf1\f51\fs20\ql of our efforts and financial resources in the identification and preclinical development of our current product candidates. Our\plain\cf1\f51\fs20\ql ability to generate product revenue, which we do not expect will occur for many years, if ever, will depend heavily on the\plain\cf1\f51\fs20\ql successful development and eventual commercialization of our product candidates, which may never occur. For example, our\plain\cf1\f51\fs20\ql research programs, including those subject to our joint venture with Bayer Healthcare and Collaboration Agreement and the Joint\plain\cf1\f51\fs20\ql Development and Commercialization Agreement, or the JDA, with Vertex, may fail to identify potential product candidates for\plain\cf1\f51\fs20\ql clinical development for a number of reasons or may fail to successfully advance any product candidates through clinical\plain\cf1\f51\fs20\ql development. Our research methodology may be unsuccessful in identifying potential product candidates, or our potential product\plain\cf1\f51\fs20\ql candidates may be shown to have harmful side effects or may have other characteristics that may make the products impractical\plain\cf1\f51\fs20\ql to manufacture, unmarketable, or unlikely to receive marketing approval. We currently generate no revenue from sales of any\plain\cf1\f51\fs20\ql product and we may never be able to develop or commercialize a marketable product.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In December 2017, we submitted CTAs in various European jurisdictions for CTX001 to begin our first clinical trial in\plain\cf1\f51\fs20\ql beta-thalassemia and plan, following a pre-IND meeting with the FDA, to file an IND with the FDA in the first half of 2018 to\plain\cf1\f51\fs20\ql begin our first clinical trial for CTX001 in sickle cell disease. The filing of future CTAs or INDs for any other product candidate\plain\cf1\f51\fs20\ql we develop is subject to the identification and selection of guide RNA with acceptable efficiency. Subject to successful\plain\cf1\f51\fs20\ql completion of preclinical toxicology testing, we also intend to file an IND for CTX101 by the end of 2018. Commencing any of\plain\cf1\f51\fs20\ql our clinical trials is also subject to acceptance by the European regulatory authorities of our CTAs, or the FDA of our INDs, and\plain\cf1\f51\fs20\ql finalizing the trial design based on discussions with the applicable regulatory authorities, including the Recombinant DNA\plain\cf1\f51\fs20\ql Advisory Committee, or RAC, of the U.S. National Institutes of Health, or NIH. In the event that the European regulatory\plain\cf1\f51\fs20\ql authorities, FDA or RAC requires us to complete additional preclinical studies or we are required to satisfy other requests, the\plain\cf1\f51\fs20\ql start of our first clinical trial for our hemoglobinopathy programs or any of our other programs may be delayed. Even after we\plain\cf1\f51\fs20\ql receive and incorporate guidance from these regulatory authorities, they could disagree that we have satisfied their requirements\plain\cf1\f51\fs20\ql to commence our clinical trial or change their position on the acceptability of our trial design or the clinical endpoints selected,\plain\cf1\f51\fs20\ql which may require us to complete additional preclinical studies or clinical trials or impose stricter approval conditions than we\plain\cf1\f51\fs20\ql currently expect.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Our product candidates will require additional preclinical and clinical development, regulatory and marketing approval in\plain\cf1\f51\fs20\ql multiple jurisdictions, obtaining manufacturing supply, capacity and expertise, building of a commercial organization, substantial\plain\cf1\f51\fs20\ql investment and significant marketing efforts before we generate any revenue from product sales. In addition, our product\plain\cf1\f51\fs20\ql development programs must be approved for marketing by the FDA, EMA or certain other health regulatory agencies, before we\plain\cf1\f51\fs20\ql may commercialize our product candidates.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The success of our product candidates will depend on several factors, including the following:
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql successful completion of clinical trials and preclinical studies;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql sufficiency of our financial and other resources to complete the necessary clinical trials and preclinical studies;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql ability to develop safe and effective delivery mechanisms for our\plain\intbl\cf1\f51\fs20\i\ql in vivo\plain\intbl\cf1\f51\fs20\ql therapeutic programs;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql ability to identify optimal RNA sequences to guide genomic editing;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql entry into collaborations to further the development of our product candidates;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql a positive recommendation of the Recombinant DNA Advisory Committee of the NIH;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql approval of CTAs or INDs for our product candidates to commence clinical trials;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\sb264\cf1\f51\fs20\qc 42\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql successful enrollment in, and completion of, clinical trials and preclinical studies;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh495
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql successful data from our clinical program that supports an acceptable risk-benefit profile of our product candidates\plain\intbl\cf1\f51\fs20\ql for the intended patient populations;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh495\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql receipt of regulatory and marketing approvals from applicable regulatory authorities;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh495
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql establishment of arrangements with third-party manufacturers for clinical supply and commercial manufacturing\plain\intbl\cf1\f51\fs20\ql and, where applicable, commercial manufacturing capabilities;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh495\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh495
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql successful development of our internal manufacturing processes and transfer to larger-scale facilities operated by\plain\intbl\cf1\f51\fs20\ql either a contract manufacturing organization, or CMO, or by us;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh495\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh495
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql establishment and maintenance of patent and trade secret protection or regulatory exclusivity for our product\plain\intbl\cf1\f51\fs20\ql candidates;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh495\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql commercial launch of our product candidates, if and when approved, whether alone or in collaboration with others;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh495
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql acceptance of the product candidates, if and when approved, by patients, the medical community and third-party\plain\intbl\cf1\f51\fs20\ql payors;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh495\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql effective competition with other therapies and treatment options;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql establishment and maintenance of healthcare coverage and adequate reimbursement;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql enforcement and defense of intellectual property rights and claims;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql maintenance of a continued acceptable safety profile of the product candidates following approval; and\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql achieving desirable medicinal properties for the intended indications.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\sb264\fi528\cf1\f51\fs20\ql Additionally, because our technology involves gene editing across multiple cell and tissue types, we are subject to many of\plain\cf1\f51\fs20\ql the challenges and risks that gene therapies face, including:
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh878
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql regulatory requirements governing gene and cell therapy products have changed frequently and may continue to\plain\intbl\cf1\f51\fs20\ql change in the future; to date, no products that involve the genetic modification of patient cells have been approved\plain\intbl\cf1\f51\fs20\ql in the United States and only one gene therapy product has been approved in the European Union;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh878\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh495
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql improper insertion of a gene sequence into a patient\u8217?s chromosome could lead to lymphoma, leukemia or\plain\intbl\cf1\f51\fs20\ql other cancers, or other aberrantly functioning cells; and\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh495\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh495
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql the FDA recommends a follow-up observation period of 15 years or longer for all patients who receive treatment\plain\intbl\cf1\f51\fs20\ql using gene therapies, and we may need to adopt and support such an observation period for our product candidates.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh495\row}}}\pard\plain\sb264\fi528\cf1\f51\fs20\ql If we do not succeed in one or more of these factors in a timely manner or at all, we could experience significant delays or\plain\cf1\f51\fs20\ql an inability to successfully commercialize our product candidates, which would materially harm our business. If we do not\plain\cf1\f51\fs20\ql receive regulatory approvals for our product candidates, we may not be able to continue our operations.\par\pard\plain\sb264\cf1\f51\fs20\qc 43\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Our CRISPR/Cas9 Gene Editing Product Candidates Are Based On A New Gene Editing Technology, Which Makes It\plain\cf1\f51\fs20\i\ql Difficult To Predict The Time And Cost Of Development And Of Subsequently Obtaining Regulatory Approval, If At All. There\plain\cf1\f51\fs20\i\ql Have Only Been A Limited Number Of Clinical Trials Of Product Candidates Based On Gene Editing Technology And No Gene\plain\cf1\f51\fs20\i\ql Editing Products Have Been Approved In The United States Or In The European Union.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql CRISPR/Cas9 gene editing technology is relatively new, and no products based on CRISPR/Cas9 or other similar gene\plain\cf1\f51\fs20\ql editing technologies have been approved in the United States or the European Union and only a limited number of clinical trials\plain\cf1\f51\fs20\ql of products based on gene editing technologies have been commenced. As such it is difficult to accurately predict the\plain\cf1\f51\fs20\ql developmental challenges we may incur for our product candidates as they proceed through product discovery or identification,\plain\cf1\f51\fs20\ql preclinical studies and clinical trials. In addition, because we have not commenced clinical trials, we have not yet been able to\plain\cf1\f51\fs20\ql assess safety in humans, and there may be long-term effects from treatment with any product candidates that we develop that we\plain\cf1\f51\fs20\ql cannot predict at this time. Any product candidates we may develop will act at the level of DNA, and, because animal DNA\plain\cf1\f51\fs20\ql differs from human DNA, testing of our product candidates in animal models may not be predictive of the results we observe in\plain\cf1\f51\fs20\ql human clinical trials of our product candidates for either safety or efficacy. Also, animal models may not exist for some of the\plain\cf1\f51\fs20\ql diseases we choose to pursue in our programs. As a result of these factors, it is more difficult for us to predict the time and cost\plain\cf1\f51\fs20\ql of product candidate development, and we cannot predict whether the application of our gene editing technology, or any similar\plain\cf1\f51\fs20\ql or competitive gene editing technologies, will result in the identification, development, and regulatory approval of any products.\plain\cf1\f51\fs20\ql There can be no assurance that any development problems we experience in the future related to our gene editing technology or\plain\cf1\f51\fs20\ql any of our research programs will not cause significant delays or unanticipated costs, or that such development problems can be\plain\cf1\f51\fs20\ql solved. Any of these factors may prevent us from completing our preclinical studies or any clinical trials that we may initiate or\plain\cf1\f51\fs20\ql commercializing any product candidates we may develop on a timely or profitable basis, if at all.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The clinical trial requirements of the FDA, the EMA and other regulatory authorities and the criteria these regulators use to\plain\cf1\f51\fs20\ql determine the safety and efficacy of a product candidate vary substantially according to the type, complexity, novelty and\plain\cf1\f51\fs20\ql intended use and market of the product candidate. No products based on gene editing technologies have been approved by\plain\cf1\f51\fs20\ql regulators. As a result, the regulatory approval process for product candidates such as ours is uncertain and may be more\plain\cf1\f51\fs20\ql expensive and take longer than the approval process for product candidates based on other, better known or more extensively\plain\cf1\f51\fs20\ql studied technologies. It is difficult to determine how long it will take or how much it will cost to obtain regulatory approvals for\plain\cf1\f51\fs20\ql our product candidates in either the United States or the European Union or how long it will take to commercialize our product\plain\cf1\f51\fs20\ql candidates. Delay or failure to obtain, or unexpected costs in obtaining, the regulatory approval necessary to bring a potential\plain\cf1\f51\fs20\ql product candidate to market could decrease our ability to generate sufficient product revenue, and our business, financial\plain\cf1\f51\fs20\ql condition, results of operations and prospects may be harmed.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql The FDA, The NIH And The EMA Have Demonstrated Caution In Their Regulation Of Gene Therapy Treatments, And\plain\cf1\f51\fs20\i\ql Ethical And Legal Concerns About Gene Therapy And Genetic Testing May Result In Additional Regulations Or Restrictions On\plain\cf1\f51\fs20\i\ql The Development And Commercialization Of Our Product Candidates, Which May Be Difficult To Predict.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql The FDA, NIH and the EMA have each expressed interest in further regulating biotechnology, including gene therapy and\plain\cf1\f51\fs20\ql genetic testing. For example, the EMA advocates a risk-based approach to the development of a gene therapy product. Agencies\plain\cf1\f51\fs20\ql at both the federal and state level in the United States, as well as the U.S. congressional committees and other governments or\plain\cf1\f51\fs20\ql governing agencies, have also expressed interest in further regulating the biotechnology industry. Such action may delay or\plain\cf1\f51\fs20\ql prevent commercialization of some or all of our product candidates. Within the broader genome product field,\plain\cf1\f51\fs20\ql uniQure\~N.V.\u8217?s Glybera has received marketing authorization from the European Commission, and to date no gene therapy\plain\cf1\f51\fs20\ql products have received marketing approval in the United States.\par\pard\plain\sb264\cf1\f51\fs20\qc 44\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Regulatory requirements in the United States and in other jurisdictions governing gene therapy products have changed\plain\cf1\f51\fs20\ql frequently and may continue to change in the future. The FDA established the Office of Cellular, Tissue and Gene Therapies\plain\cf1\f51\fs20\ql within its Center for Biologics Evaluation and Research to consolidate the review of gene therapy and related products, and\plain\cf1\f51\fs20\ql established the Cellular, Tissue and Gene Therapies Advisory Committee to advise this review. Prior to submitting an IND, our\plain\cf1\f51\fs20\ql human clinical trials are subject to review by the NIH Office of Biotechnology Activities, or OBA, Recombinant DNA Advisory\plain\cf1\f51\fs20\ql Committee, or the RAC. Following an initial review, RAC members make a recommendation as to whether the protocol raises\plain\cf1\f51\fs20\ql important scientific, safety, medical, ethical or social issues that warrant in-depth discussion at the RAC\u8217?s quarterly\plain\cf1\f51\fs20\ql meetings. Even though the FDA decides whether individual gene therapy protocols may proceed under an IND, the RAC\u8217?s\plain\cf1\f51\fs20\ql recommendations are shared with the FDA and the RAC public review process, if undertaken, can delay the initiation of a\plain\cf1\f51\fs20\ql clinical trial, even if the FDA has reviewed the trial design and details and has not objected to its initiation or has notified the\plain\cf1\f51\fs20\ql sponsor that the study may begin. Conversely, the FDA can put an IND on a clinical hold even if the RAC has provided a\plain\cf1\f51\fs20\ql favorable review or has recommended against an in-depth, public review. Moreover, under guidelines published by the NIH,\plain\cf1\f51\fs20\ql patient enrollment in our future gene editing clinical trials cannot begin until the investigator for such clinical trial has received a\plain\cf1\f51\fs20\ql letter from the OBA indicating that the RAC review process has been completed; and Institutional Biosafety Committee, or IBC,\plain\cf1\f51\fs20\ql approval as well as all other applicable regulatory authorizations have been obtained. In addition to the government regulators,\plain\cf1\f51\fs20\ql the IBC and institutional review board, or IRB, of each institution at which we conduct clinical trials of our product candidates,\plain\cf1\f51\fs20\ql or a central IRB if appropriate, would need to review the proposed clinical trial to assess the safety of the trial. In addition,\plain\cf1\f51\fs20\ql adverse developments in clinical trials of gene therapy products conducted by others may cause the FDA or other oversight\plain\cf1\f51\fs20\ql bodies to change the requirements for approval of any of our product candidates. Similarly, the EMA governs the development of\plain\cf1\f51\fs20\ql gene therapies in the European Union and may issue new guidelines concerning the development and marketing authorization for\plain\cf1\f51\fs20\ql gene therapy products and require that we comply with these new guidelines. These regulatory review agencies and committees\plain\cf1\f51\fs20\ql and the new requirements or guidelines they promulgate may lengthen the regulatory review process, require us to perform\plain\cf1\f51\fs20\ql additional studies or trials, increase our development costs, lead to changes in regulatory positions and interpretations, delay or\plain\cf1\f51\fs20\ql prevent approval and commercialization of our product candidates or lead to significant post-approval limitations or restrictions.\plain\cf1\f51\fs20\ql As we advance our product candidates, we will be required to consult with these regulatory agencies and committees and comply\plain\cf1\f51\fs20\ql with applicable requirements and guidelines. If we fail to do so, we may be required to delay or discontinue development of such\plain\cf1\f51\fs20\ql product candidates. These additional processes may result in a review and approval process that is longer than we otherwise\plain\cf1\f51\fs20\ql would have expected. Delays as a result of an increased or lengthier regulatory approval process or further restrictions on the\plain\cf1\f51\fs20\ql development of our product candidates can be costly and could negatively impact our or our collaborators\u8217? ability to\plain\cf1\f51\fs20\ql complete clinical trials and commercialize our current and future product candidates in a timely manner, if at all.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql If Any Of The Product Candidates We May Develop Or The Delivery Modes We Rely On Cause Undesirable Side Effects,\plain\cf1\f51\fs20\i\ql It Could Delay Or Prevent Their Regulatory Approval, Limit The Commercial Potential Or Result In Significant Negative\plain\cf1\f51\fs20\i\ql Consequences Following Any Potential Marketing Approval.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Product candidates we may develop may be associated with undesirable side effects, unexpected characteristics or other\plain\cf1\f51\fs20\ql serious adverse events, including off-target cuts of DNA, or the introduction of cuts in DNA at locations other than the target\plain\cf1\f51\fs20\ql sequence. These off-target cuts could lead to disruption of a gene or a genetic regulatory sequence at an unintended site in the\plain\cf1\f51\fs20\ql DNA, or, in those instances where we also provide a segment of DNA to serve as a repair template, it is possible that following\plain\cf1\f51\fs20\ql off-target cut events, DNA from such repair template could be integrated into the genome at an unintended site, potentially\plain\cf1\f51\fs20\ql disrupting another important gene or genomic element. There also is the potential risk of delayed adverse events following\plain\cf1\f51\fs20\ql exposure to gene editing therapy due to persistent biologic activity of the genetic material or other components of products used\plain\cf1\f51\fs20\ql to carry the genetic material. Possible adverse side effects that could occur with treatment with gene editing products include an\plain\cf1\f51\fs20\ql immunologic reaction after administration which could substantially limit the effectiveness of the treatment. Additionally,\plain\cf1\f51\fs20\ql immunotherapy, and its method of action of harnessing the body\u8217?s immune system, is powerful and could lead to serious\plain\cf1\f51\fs20\ql side effects that we only discover in clinical trials. Unforeseen side effects could arise either during clinical development or, if\plain\cf1\f51\fs20\ql such side effects are more rare, after our product candidates have been approved by regulatory authorities and the approved\plain\cf1\f51\fs20\ql product has been marketed, resulting in the exposure of additional patients. If our CRISPR/Cas9 gene editing technology\plain\cf1\f51\fs20\ql demonstrates a similar effect, we may decide or be required to halt or delay preclinical development or clinical development of\plain\cf1\f51\fs20\ql our product candidates. In addition to serious adverse events or side effects caused by any product candidate we may develop;\plain\cf1\f51\fs20\ql the administration process or related procedures also can cause undesirable side effects. If any such events occur, our clinical\plain\cf1\f51\fs20\ql trials could be suspended or terminated.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql If in the future we are unable to demonstrate that such adverse events were caused by factors other than our product\plain\cf1\f51\fs20\ql candidate, the FDA, EMA or other comparable health regulatory authorities could order us to cease further clinical studies of, or\plain\cf1\f51\fs20\ql deny approval of, any product candidates we are able to develop for any or all targeted indications. Even if we are able to\plain\cf1\f51\fs20\ql demonstrate that all future serious adverse events are not product-related, such occurrences could affect patient recruitment or the\plain\cf1\f51\fs20\ql ability of enrolled patients to complete the trial. Moreover, if we elect, or are required, to delay, suspend or terminate any clinical\plain\cf1\f51\fs20\ql trial of any product candidate we may develop, the commercial prospects of such product candidates may be harmed and our\plain\cf1\f51\fs20\ql ability to generate product revenues from any of these product candidates may be delayed or eliminated. Any of these\plain\cf1\f51\fs20\ql occurrences may harm our ability to identify and develop product candidates, and may harm our business, financial condition,\plain\cf1\f51\fs20\ql result of operations and prospects significantly.\par\pard\plain\sb264\cf1\f51\fs20\qc 45\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Additionally, if we successfully develop a product candidate and it receives marketing approval, the FDA could require us\plain\cf1\f51\fs20\ql to adopt a Risk Evaluation and Mitigation Strategy, or REMS, to ensure that the benefits of treatment with such product\plain\cf1\f51\fs20\ql candidate outweighs the risks for each potential patient, which may include, among other things, a medication guide outlining the\plain\cf1\f51\fs20\ql risks of the product for distribution to patients, a communication plan to health care practitioners, extensive patient monitoring, or\plain\cf1\f51\fs20\ql distribution systems and processes that are highly controlled, restrictive, and more costly than what is typical for the industry.\plain\cf1\f51\fs20\ql Furthermore, if we or others later identify undesirable side effects caused by any product candidate that we to develop, several\plain\cf1\f51\fs20\ql potentially significant negative consequences could result, including:
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql regulatory authorities may revoke licenses or suspend, vary or withdraw approvals of such product candidate;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql regulatory authorities may require additional warnings on the label;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql we may be required to change the way a product candidate is administered or conduct additional clinical trials;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql we could be sued and held liable for harm caused to patients; and\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql our reputation may suffer.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}\pard\plain\sb264\fi528\cf1\f51\fs20\ql Any of these events could prevent us from achieving or maintaining market acceptance of our CRISPR/Cas9 technology\plain\cf1\f51\fs20\ql and any product candidates we may identify and develop and could have a material adverse effect on our business, financial\plain\cf1\f51\fs20\ql condition, results of operations and prospects.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql If We Experience Delays Or Difficulties In The Enrollment Of Patients In Clinical Trials, Our Receipt Of Necessary\plain\cf1\f51\fs20\i\ql Regulatory Approvals Could Be Delayed Or Prevented.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We or our collaborators may not be able to initiate or continue clinical trials for any product candidates we identify or\plain\cf1\f51\fs20\ql develop if we are unable to locate and enroll a sufficient number of eligible patients to participate in these trials as required by\plain\cf1\f51\fs20\ql the FDA or analogous regulatory authorities outside the United States, or as needed to provide appropriate statistical power for a\plain\cf1\f51\fs20\ql given trial. Enrollment may be particularly challenging for any rare genetically defined diseases we may target in the future. In\plain\cf1\f51\fs20\ql addition, if patients are unwilling to participate in our gene editing trials because of negative publicity from adverse events\plain\cf1\f51\fs20\ql related to the biotechnology, gene therapy or gene editing fields, competitive clinical trials for similar patient populations, clinical\plain\cf1\f51\fs20\ql trials in competing products, or for other reasons, the timeline for recruiting patients, conducting studies and obtaining regulatory\plain\cf1\f51\fs20\ql approval of any product candidates we may develop may be delayed. Moreover, some of our competitors may have ongoing\plain\cf1\f51\fs20\ql clinical trials for product candidates that would treat the same indications as any product candidates we may develop, and patients\plain\cf1\f51\fs20\ql who would otherwise be eligible for our clinical trials may instead enroll in clinical trials of our competitors\u8217? product\plain\cf1\f51\fs20\ql candidates.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Patient enrollment is also affected by other factors, including:
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql severity of the disease under investigation;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql size of the patient population and process for identifying subjects;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql design of the trial protocol;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql availability and efficacy of approved medications for the disease under investigation;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql availability of genetic testing for potential patients;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql ability to obtain and maintain subject consent;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql risk that enrolled subjects will drop out before completion of the trial;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql eligibility and exclusion criteria for the trial in question;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql perceived risks and benefits of the product candidate under trial;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql perceived risks and benefits of gene editing and cellular therapies as therapeutic approaches;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql efforts to facilitate timely enrollment in clinical trials;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql patient referral practices of physicians;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql ability to monitor patients adequately during and after treatment; and\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql proximity and availability of clinical trial sites for prospective patients.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\sb264\cf1\f51\fs20\qc 46\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Enrollment delays in our clinical trials may result in increased development costs for any product candidates we may\plain\cf1\f51\fs20\ql develop, which would cause the value of our Company to decline and limit our ability to obtain additional financing. If we or\plain\cf1\f51\fs20\ql our collaborators have difficulty enrolling a sufficient number of patients to conduct our clinical trials as planned, we may need\plain\cf1\f51\fs20\ql to delay, limit, or terminate ongoing or planned clinical trials, any of which would have an adverse effect on our business,\plain\cf1\f51\fs20\ql financial condition, results of operations, and prospects.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Positive Results From Early Preclinical Studies Of Our Product Candidates Are Not Necessarily Predictive Of The Results\plain\cf1\f51\fs20\i\ql Of Later Preclinical Studies And Any Future Clinical Trials Of Our Product Candidates. If We Cannot Replicate The Positive\plain\cf1\f51\fs20\i\ql Results From Our Earlier Preclinical Studies Of Our Product Candidates In Our Later Preclinical Studies And Future Clinical\plain\cf1\f51\fs20\i\ql Trials, We May Be Unable To Successfully Develop, Obtain Regulatory Approval For And Commercialize Our Product\plain\cf1\f51\fs20\i\ql Candidates.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Any positive results from our preclinical studies of our product candidates may not necessarily be predictive of the results\plain\cf1\f51\fs20\ql from required later preclinical studies and clinical trials. Similarly, even if we are able to complete our planned preclinical studies\plain\cf1\f51\fs20\ql or any future clinical trials of our product candidates according to our current development timeline, the positive results from\plain\cf1\f51\fs20\ql such preclinical studies and clinical trials of our product candidates may not be replicated in subsequent preclinical studies or\plain\cf1\f51\fs20\ql clinical trial results.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Many companies in the pharmaceutical and biotechnology industries have suffered significant setbacks in late-stage clinical\plain\cf1\f51\fs20\ql trials after achieving positive results in early-stage development and we cannot be certain that we will not face similar setbacks.\plain\cf1\f51\fs20\ql These setbacks have been caused by, among other things, preclinical and other nonclinical findings made while clinical trials\plain\cf1\f51\fs20\ql were underway or safety or efficacy observations made in preclinical studies and clinical trials, including previously unreported\plain\cf1\f51\fs20\ql adverse events. Moreover, preclinical, nonclinical and clinical data are often susceptible to varying interpretations and analyses\plain\cf1\f51\fs20\ql and many companies that believed their product candidates performed satisfactorily in preclinical studies and clinical trials\plain\cf1\f51\fs20\ql nonetheless failed to obtain FDA or EMA approval.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Even If We Complete The Necessary Preclinical Studies And Clinical Trials, The Marketing Approval Process Is Expensive,\plain\cf1\f51\fs20\i\ql Time-Consuming, And Uncertain And May Prevent Us From Obtaining Approvals For The Commercialization Of Any Product\plain\cf1\f51\fs20\i\ql Candidates We May Develop. If We Are Not Able To Obtain, Or If There Are Delays In Obtaining, Required Regulatory\plain\cf1\f51\fs20\i\ql Approvals, We Will Not Be Able To Commercialize, Or Will Be Delayed In Commercializing, Product Candidates We May\plain\cf1\f51\fs20\i\ql Develop, And Our Ability To Generate Revenue Will Be Materially Impaired.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Any product candidates we may develop and the activities associated with their development and commercialization,\plain\cf1\f51\fs20\ql including their design, testing, manufacture, safety, efficacy, recordkeeping, labeling, storage, approval, advertising, promotion,\plain\cf1\f51\fs20\ql sale, and distribution, are subject to comprehensive regulation by the FDA and other regulatory authorities in the United States,\plain\cf1\f51\fs20\ql by EMA in the European Union and by comparable authorities in other countries. Failure to obtain marketing approval for a\plain\cf1\f51\fs20\ql product candidate will prevent us from commercializing the product candidate in a given jurisdiction. We have not received\plain\cf1\f51\fs20\ql approval or clearance to market any product candidates from regulatory authorities in any jurisdiction and it is possible that none\plain\cf1\f51\fs20\ql of our product candidates or any product candidates we may seek to develop in the future will ever obtain regulatory approval or\plain\cf1\f51\fs20\ql clearance. We have only limited experience in filing and supporting the applications necessary to gain marketing approvals and\plain\cf1\f51\fs20\ql expect to rely on third-party contract research organizations, or CROs, or regulatory consultants to assist us in this process.\plain\cf1\f51\fs20\ql Securing regulatory approval requires the submission of extensive preclinical and clinical data and supporting information to the\plain\cf1\f51\fs20\ql various regulatory authorities for each therapeutic indication to establish the biologic product candidate\u8217?s safety, purity,\plain\cf1\f51\fs20\ql efficacy and potency. Securing regulatory approval also requires the submission of information about the product manufacturing\plain\cf1\f51\fs20\ql process to, and inspection of manufacturing facilities by, the relevant regulatory authority. Any product candidates we develop\plain\cf1\f51\fs20\ql may not be effective, may be only moderately effective, or may prove to have undesirable or unintended side effects, toxicities or\plain\cf1\f51\fs20\ql other characteristics that may preclude our obtaining marketing approval or prevent or limit commercial use.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The process of obtaining marketing approvals, both in the United States and in other jurisdictions, is expensive, may take\plain\cf1\f51\fs20\ql many years if additional clinical trials are required, if approval is obtained at all, and can vary substantially based upon a variety\plain\cf1\f51\fs20\ql of factors, including the type, complexity, and novelty of the product candidates involved. Changes in marketing approval policies\plain\cf1\f51\fs20\ql during the development period, changes in or the enactment of additional statutes or regulations, or changes in regulatory review\plain\cf1\f51\fs20\ql for each submitted product application, may cause delays in the approval or rejection of an application. The FDA and comparable\plain\cf1\f51\fs20\ql authorities in other countries have substantial discretion in the approval process and may refuse to accept any application or may\plain\cf1\f51\fs20\ql decide that our data are insufficient for approval and require additional preclinical, clinical or other studies. In addition, varying\plain\cf1\f51\fs20\ql interpretations of the data obtained from preclinical and clinical testing could delay, limit, or prevent marketing approval of a\plain\cf1\f51\fs20\ql product candidate. Any marketing approval we ultimately obtain may be limited or subject to restrictions or post-approval\plain\cf1\f51\fs20\ql commitments that render the approved product not commercially viable.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb44\fi528\cf1\f51\fs20\ql If we experience delays in obtaining approval or if we fail to obtain approval of any product candidates we may develop,\plain\cf1\f51\fs20\ql the commercial prospects for those product candidates may be harmed, and our ability to generate revenues will be materially\plain\cf1\f51\fs20\ql impaired.\par\pard\plain\sb264\cf1\f51\fs20\qc 47\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql We May Never Obtain FDA Approval For Any Of Our Product Candidates In The United States, And Even If We Do, We\plain\cf1\f51\fs20\i\ql May Never Obtain Approval For Or Commercialize Any Of Our Product Candidates In Any Other Jurisdiction, Which Would\plain\cf1\f51\fs20\i\ql Limit Our Ability To Realize Their Full Market Potential.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql In order to eventually market any of our product candidates in any particular jurisdiction, we must establish and comply\plain\cf1\f51\fs20\ql with numerous and varying regulatory requirements on a jurisdiction-by-jurisdiction basis regarding safety and efficacy.\plain\cf1\f51\fs20\ql Approval by the FDA in the United States, if obtained, does not ensure approval by regulatory authorities in other countries or\plain\cf1\f51\fs20\ql jurisdictions. In addition, clinical trials conducted in one country may not be accepted by regulatory authorities in other countries,\plain\cf1\f51\fs20\ql and regulatory approval in one country does not guarantee regulatory approval in any other country. Approval processes vary\plain\cf1\f51\fs20\ql among countries and can involve additional product testing and validation and additional administrative review periods. Seeking\plain\cf1\f51\fs20\ql regulatory approval in multiple jurisdictions could result in difficulties and costs for us and require additional preclinical studies\plain\cf1\f51\fs20\ql or clinical trials which could be costly and time-consuming. Regulatory requirements can vary widely from country to country\plain\cf1\f51\fs20\ql and could delay or prevent the introduction of our products in certain countries. Regulatory approval processes outside the United\plain\cf1\f51\fs20\ql States involve all of the risks associated with FDA approval. We do not have any product candidates approved for sale in any\plain\cf1\f51\fs20\ql jurisdiction, including international markets, and we do not have experience in obtaining regulatory approval in international\plain\cf1\f51\fs20\ql markets. If we fail to comply with regulatory requirements in international markets or to obtain and maintain required approvals,\plain\cf1\f51\fs20\ql or if regulatory approvals in international markets are delayed, our target market will be reduced and our ability to realize the full\plain\cf1\f51\fs20\ql market potential of our products will be unrealized.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Gene Editing Products Are Novel And May Be Complex And Difficult To Manufacture. We Could Experience\plain\cf1\f51\fs20\i\ql Manufacturing Problems That Result In Delays In The Development Or Commercialization Of Our Product Candidates Or\plain\cf1\f51\fs20\i\ql Otherwise Harm Our Business.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql The manufacturing process used to produce CRISPR/Cas9-based product candidates may be complex, as they are novel\plain\cf1\f51\fs20\ql and have not been validated for clinical and commercial production. Several factors could cause production interruptions,\plain\cf1\f51\fs20\ql including equipment malfunctions, facility contamination, raw material shortages or contamination, natural disasters, disruption in\plain\cf1\f51\fs20\ql utility services, human error or disruptions in the operations of our suppliers.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Our product candidates will require processing steps that are more complex than those required for most small molecule\plain\cf1\f51\fs20\ql drugs. Moreover, unlike small molecules, the physical and chemical properties of biologics generally cannot be fully\plain\cf1\f51\fs20\ql characterized. As a result, assays of the finished product may not be sufficient to ensure that the product will perform in the\plain\cf1\f51\fs20\ql intended manner. Accordingly, we will employ multiple steps to control the manufacturing process to assure that the process\plain\cf1\f51\fs20\ql works and the product candidate is made strictly and consistently in compliance with the process. Problems with the\plain\cf1\f51\fs20\ql manufacturing process, even minor deviations from the normal process, could result in product defects or manufacturing failures\plain\cf1\f51\fs20\ql that result in lot failures, product recalls, product liability claims or insufficient inventory. We may encounter problems achieving\plain\cf1\f51\fs20\ql adequate quantities and quality of clinical grade materials that meet FDA, the EMA or other applicable standards or specifications\plain\cf1\f51\fs20\ql with consistent and acceptable production yields and costs.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In addition, the FDA, the EMA and other health regulatory authorities may require us to submit samples of any lot of any\plain\cf1\f51\fs20\ql approved product together with the protocols showing the results of applicable tests at any time. Under some circumstances, the\plain\cf1\f51\fs20\ql FDA, the EMA or other health regulatory authorities may require that we not distribute a lot until the relevant agency authorizes\plain\cf1\f51\fs20\ql its release. Slight deviations in the manufacturing process, including those affecting quality attributes and stability, may result in\plain\cf1\f51\fs20\ql unacceptable changes in the product that could result in lot failures or product recalls. Lot failures or product recalls could cause\plain\cf1\f51\fs20\ql us to delay product launches or clinical trials, which could be costly to us and otherwise harm our business, financial condition,\plain\cf1\f51\fs20\ql results of operations and prospects. Problems in our manufacturing process could restrict our ability to meet market demand for\plain\cf1\f51\fs20\ql our products.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We also may encounter problems hiring and retaining directly or through contract manufacturing organizations the\plain\cf1\f51\fs20\ql experienced scientific, quality-control and manufacturing personnel needed to operate our manufacturing processes, which could\plain\cf1\f51\fs20\ql result in delays in production or difficulties in maintaining compliance with applicable regulatory requirements. Any problems in\plain\cf1\f51\fs20\ql our manufacturing process or facilities could make us a less attractive collaborator for potential partners, including larger\plain\cf1\f51\fs20\ql pharmaceutical companies and academic research institutions, which could limit our access to additional attractive development\plain\cf1\f51\fs20\ql programs.\~\~\par\pard\plain\sb264\cf1\f51\fs20\qc 48\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Adverse Public Perception Of Gene Editing And Cellular Therapy Products May Negatively Impact Demand For, Or\plain\cf1\f51\fs20\i\ql Regulatory Approval Of, Our Product Candidates.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Our product candidates involve editing the human genome. The clinical and commercial success of our product candidates\plain\cf1\f51\fs20\ql will depend in part on public acceptance of the use of gene editing therapies for the prevention or treatment of human diseases.\plain\cf1\f51\fs20\ql Public attitudes may be influenced by claims that gene editing is unsafe, unethical, or immoral, and, consequently, our products\plain\cf1\f51\fs20\ql may not gain the acceptance of the public or the medical community. Negative public reaction to gene therapy in general could\plain\cf1\f51\fs20\ql result in greater government regulation and stricter labeling requirements of gene editing products, including any of our product\plain\cf1\f51\fs20\ql candidates, and could cause a decrease in the demand for any products we may develop. Adverse public attitudes may adversely\plain\cf1\f51\fs20\ql impact our ability to enroll clinical trials. Moreover, our success will depend upon physicians prescribing, and their patients being\plain\cf1\f51\fs20\ql willing to receive, treatments that involve the use of product candidates we may develop in lieu of, or in addition to, existing\plain\cf1\f51\fs20\ql treatments with which they are already familiar and for which greater clinical data may be available.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In particular, gene editing technology is subject to public debate and heightened regulatory scrutiny due to ethical concerns\plain\cf1\f51\fs20\ql relating to the application of gene editing technology to human embryos or the human germline. For example, in April 2016,\plain\cf1\f51\fs20\ql Chinese scientists reported on their attempts to edit the genome of human embryos to modify the gene for hemoglobin beta. This\plain\cf1\f51\fs20\ql is the gene in which a mutation occurs in patients with the inherited blood disorder beta-thalassemia. Although this research was\plain\cf1\f51\fs20\ql purposefully conducted in embryos that were not viable, the work prompted calls for a moratorium or other types of restrictions\plain\cf1\f51\fs20\ql on gene editing of human eggs, sperm, and embryos. The Alliance for Regenerative Medicine in Washington, D.C. has called for\plain\cf1\f51\fs20\ql a voluntary moratorium on the use of gene editing technologies, including CRISPR/Cas9, in research that involves altering human\plain\cf1\f51\fs20\ql embryos or human germline cells. Similarly, the NIH has announced that it would not fund any use of gene editing technologies\plain\cf1\f51\fs20\ql in human embryos, noting that there are multiple existing legislative and regulatory prohibitions against such work, including the\plain\cf1\f51\fs20\ql Dickey-Wicker Amendment, which prohibits the use of appropriated funds for the creation of human embryos for research\plain\cf1\f51\fs20\ql purposes or for research in which human embryos are destroyed. Laws in the United Kingdom prohibit genetically modified\plain\cf1\f51\fs20\ql embryos from being implanted into women, but embryos can be altered in research labs under license from the Human\plain\cf1\f51\fs20\ql Fertilisation and Embryology Authority. Research on embryos is more tightly controlled in many other European countries.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Although we do not use our technologies to edit human embryos or the human germline, such public debate about the use\plain\cf1\f51\fs20\ql of gene editing technologies in human embryos and heightened regulatory scrutiny could prevent or delay our development of\plain\cf1\f51\fs20\ql product candidates. More restrictive government regulations or negative public opinion would have a negative effect on our\plain\cf1\f51\fs20\ql business or financial condition and may delay or impair our development and commercialization of product candidates or demand\plain\cf1\f51\fs20\ql for any products we may develop. Adverse events in our preclinical studies or clinical trials or those of our competitors or of\plain\cf1\f51\fs20\ql academic researchers utilizing gene editing technologies, even if not ultimately attributable to product candidates we may identify\plain\cf1\f51\fs20\ql and develop, and the resulting publicity could result in increased governmental regulation, unfavorable public perception, potential\plain\cf1\f51\fs20\ql regulatory delays in the testing or approval of potential product candidates we may identify and develop, stricter labeling\plain\cf1\f51\fs20\ql requirements for those product candidates that are approved, and a decrease in demand for any such product candidates.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql If, In The Future, We Are Unable To Establish Sales And Marketing Capabilities Or Enter Into Agreements With Third\plain\cf1\f51\fs20\i\ql Parties To Sell And Market Products Based On Our Technologies, We May Not Be Successful In Commercializing Our Products\plain\cf1\f51\fs20\i\ql If And When Any Products Candidates Are Approved And We May Not Be Able To Generate Any Revenue.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We do not currently have a sales or marketing infrastructure and, as a company, have no experience in the sale, marketing\plain\cf1\f51\fs20\ql or distribution of therapeutic products. To achieve commercial success for any approved product candidate for which we retain\plain\cf1\f51\fs20\ql sales and marketing responsibilities, we must build our sales, marketing, managerial and other non-technical capabilities or make\plain\cf1\f51\fs20\ql arrangements with third parties to perform these services. In the future, we may choose to build a focused sales and marketing\plain\cf1\f51\fs20\ql infrastructure to sell, or participate in sales activities with our collaborators for, some of our product candidates if any are\plain\cf1\f51\fs20\ql approved.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql There are risks involved with both establishing our own sales and marketing capabilities and entering into arrangements\plain\cf1\f51\fs20\ql with third parties to perform these services. For example, recruiting and training a sales force is expensive and time consuming\plain\cf1\f51\fs20\ql and could delay any product launch. If the commercial launch of a product candidate for which we recruit a sales force and\plain\cf1\f51\fs20\ql establish marketing capabilities is delayed or does not occur for any reason, we would have prematurely or unnecessarily incurred\plain\cf1\f51\fs20\ql these commercialization expenses. This may be costly and our investment would be lost if we cannot retain or reposition our\plain\cf1\f51\fs20\ql sales and marketing personnel.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Factors that may inhibit our efforts to commercialize our product candidates on our own include:
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql our inability to recruit, train and retain adequate numbers of effective sales and marketing personnel;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the inability of sales personnel to obtain access to physicians or persuade adequate numbers of physicians to\plain\intbl\cf1\f51\fs20\ql prescribe any future product that we may develop;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}\pard\plain\sb264\cf1\f51\fs20\qc 49\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
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{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\pard\plain\intbl\sb132\cf1\f51\fs20\ql the lack of complementary treatments to be offered by sales personnel, which may put us at a competitive\plain\intbl\cf1\f51\fs20\ql disadvantage relative to companies with more extensive product lines; and\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql unforeseen costs and expenses associated with creating an independent sales and marketing organization.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}\pard\plain\sb264\fi528\cf1\f51\fs20\ql If we enter into arrangements with third parties to perform sales, marketing and distribution services, our product revenue\plain\cf1\f51\fs20\ql or the profitability to us from these revenue streams is likely to be lower than if we were to market and sell any product\plain\cf1\f51\fs20\ql candidates that we develop ourselves. In addition, we may not be successful in entering into arrangements with third parties to\plain\cf1\f51\fs20\ql sell and market our product candidates or may be unable to do so on terms that are favorable to us. We likely will have little\plain\cf1\f51\fs20\ql control over such third parties and any of them may fail to devote the necessary resources and attention to sell and market our\plain\cf1\f51\fs20\ql product candidates effectively. If we do not establish sales and marketing capabilities successfully, either on our own or in\plain\cf1\f51\fs20\ql collaboration with third parties, we may not be successful in commercializing our product candidates. Further, our business,\plain\cf1\f51\fs20\ql results of operations, financial condition and prospects will be materially adversely affected.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Even If We, Or Any Collaborators We May Have, Obtain Marketing Approvals For Any Product Candidates We Develop,\plain\cf1\f51\fs20\i\ql The Terms Of Approvals And Ongoing Regulation Of Our Products Could Require The Substantial Expenditure Of Resources\plain\cf1\f51\fs20\i\ql And May Limit How We, Or They, Manufacture And Market Our Products, Which Could Materially Impair Our Ability To\plain\cf1\f51\fs20\i\ql Generate Revenue.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Any product candidate for which we obtain marketing approval, along with the manufacturing processes, post-approval\plain\cf1\f51\fs20\ql clinical data, labeling, advertising, and promotional activities for such product, will be subject to continual requirements of and\plain\cf1\f51\fs20\ql review by the FDA and other regulatory authorities. These requirements include submissions of safety and other post-marketing\plain\cf1\f51\fs20\ql information and reports, registration and listing requirements, current Good Manufacturing Practice, or cGMP, requirements\plain\cf1\f51\fs20\ql relating to quality control, quality assurance and corresponding maintenance of records and documents and requirements regarding\plain\cf1\f51\fs20\ql recordkeeping. Even if marketing approval of a product candidate is granted, the approval may be subject to limitations on the\plain\cf1\f51\fs20\ql indicated uses for which the product may be marketed or to the conditions of approval, or contain requirements for costly\plain\cf1\f51\fs20\ql post-marketing testing and surveillance to monitor the safety or efficacy of the product. The FDA also may place other\plain\cf1\f51\fs20\ql conditions on approvals including the requirement for a REMS to assure the safe use of the product. If the FDA concludes a\plain\cf1\f51\fs20\ql REMS is needed, the sponsor of the Biologics License Application, or BLA, must submit a proposed REMS before it can obtain\plain\cf1\f51\fs20\ql approval. A REMS could include medication guides, physician communication plans, or elements to assure safe use, such as\plain\cf1\f51\fs20\ql restricted distribution methods, patient registries and other risk minimization tools.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Accordingly, assuming we, or any collaborators we may have, receive marketing approval for one or more product\plain\cf1\f51\fs20\ql candidates we develop, we, and such collaborators, and our and their contract manufacturers will continue to expend time,\plain\cf1\f51\fs20\ql money, and effort in all areas of regulatory compliance, including manufacturing, production, product surveillance, and quality\plain\cf1\f51\fs20\ql control. If we and such collaborators are not able to comply with post-approval regulatory requirements, we and such\plain\cf1\f51\fs20\ql collaborators could have the marketing approvals for our products withdrawn by regulatory authorities and our, or such\plain\cf1\f51\fs20\ql collaborators\u8217?, ability to market any future products could be limited, which could adversely affect our ability to achieve\plain\cf1\f51\fs20\ql or sustain profitability. Further, the cost of compliance with post-approval regulations may have a negative effect on our\plain\cf1\f51\fs20\ql business, operating results, financial condition, and prospects.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Any Product Candidate For Which We Obtain Marketing Approval Could Be Subject To Restrictions Or Withdrawal From\plain\cf1\f51\fs20\i\ql The Market, And We May Be Subject To Substantial Penalties If We Fail To Comply With Regulatory Requirements Or If We\plain\cf1\f51\fs20\i\ql Experience Unanticipated Problems With Our Products, When And If Any Of Them Are Approved.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql The FDA and other regulatory agencies closely regulate the post-approval marketing and promotion of biologics to ensure\plain\cf1\f51\fs20\ql that they are marketed only for the approved indications and in accordance with the provisions of the approved labeling. The\plain\cf1\f51\fs20\ql FDA and other regulatory agencies impose stringent restrictions on manufacturers\u8217? communications regarding off-label\plain\cf1\f51\fs20\ql use, and if we do not market our products for their approved indications, we may be subject to enforcement action for off-label\plain\cf1\f51\fs20\ql marketing by the FDA and other federal and state enforcement agencies, including the United States Department of Justice.\plain\cf1\f51\fs20\ql Violation of the Federal Food, Drug, and Cosmetic Act and other statutes, including the False Claims Act, relating to the\plain\cf1\f51\fs20\ql promotion and advertising of prescription products may also lead to investigations or allegations of violations of federal and state\plain\cf1\f51\fs20\ql health care fraud and abuse laws and state consumer protection laws.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In addition, later discovery of previously unknown problems with a product candidate, including adverse events of\plain\cf1\f51\fs20\ql unanticipated severity or frequency, or with our manufacturing processes, or failure to comply with regulatory requirements, may\plain\cf1\f51\fs20\ql result in, among other things:
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{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
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{\trowd\cellx432\cellx1116\cellx10800\trrh495
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{\trowd\cellx432\cellx1116\cellx10800\trrh495\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql refusal to approve pending applications or supplements to approved applications that we submit;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql fines, restitution, or disgorgement of profits or revenue;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql suspension or withdrawal of marketing approvals or revocation of biologics licenses;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
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{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql product seizure or detention; and\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql injunctions or the imposition of civil or criminal penalties.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\sb264\fi528\cf1\f51\fs20\ql The FDA\u8217?s policies may change and additional government regulations may be enacted that could prevent, limit or\plain\cf1\f51\fs20\ql delay regulatory approval of our product candidates. If we are slow or unable to adapt to changes in existing requirements or the\plain\cf1\f51\fs20\ql adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, we may lose any marketing\plain\cf1\f51\fs20\ql approval that we may have obtained, which would adversely affect our business, prospects and ability to achieve or sustain\plain\cf1\f51\fs20\ql profitability.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Any government investigation of alleged violations of law could require us to expend significant time and resources in\plain\cf1\f51\fs20\ql response and could generate negative publicity. The occurrence of any event or penalty described above may also inhibit our\plain\cf1\f51\fs20\ql ability to commercialize any product candidates we may develop and adversely affect our business, financial condition, results of\plain\cf1\f51\fs20\ql operations, and prospects.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql The Commercial Success Of Any Of Our Product Candidates Will Depend Upon Its Degree Of Market Acceptance By\plain\cf1\f51\fs20\i\ql Physicians, Patients, Third-party Payors And Others In The Medical Community.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Ethical, social and legal concerns about gene therapy could result in additional regulations restricting or prohibiting our\plain\cf1\f51\fs20\ql products. Even with the requisite approvals from FDA in the United States, the EMA in the European Union and other regulatory\plain\cf1\f51\fs20\ql authorities internationally, the commercial success of our product candidates will depend, in significant part, on the acceptance of\plain\cf1\f51\fs20\ql physicians, patients and health care payors of gene therapy products in general, and our product candidates in particular, as\plain\cf1\f51\fs20\ql medically necessary, cost-effective and safe. Any product that we commercialize may not gain acceptance by physicians,\plain\cf1\f51\fs20\ql patients, health care payors and others in the medical community. The degree of market acceptance of gene therapy products and,\plain\cf1\f51\fs20\ql in particular, our product candidates, if approved for commercial sale, will depend on several factors, including:
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{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql the potential and perceived advantages of product candidates over alternative treatments;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
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{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql the clinical indications for which the product candidate is approved by FDA or the EMA;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql patient awareness of, and willingness to seek, genotyping;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql the willingness of physicians to prescribe new therapies;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql the willingness of the target patient population to try new therapies;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh495
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql product labeling or product insert requirements of FDA, the EMA or other regulatory authorities, including any\plain\intbl\cf1\f51\fs20\ql limitations or warnings contained in a product\u8217?s approved labeling;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\sb264\cf1\f51\fs20\qc 51\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
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\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql the timing of market introduction of competitive products;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql publicity concerning our products or competing products and treatments; and\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql sufficient third-party payor coverage and reimbursement.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\sb264\fi528\cf1\f51\fs20\ql Even if a potential product displays a favorable efficacy and safety profile in preclinical studies and future clinical trials,\plain\cf1\f51\fs20\ql market acceptance of the product will not be fully known until after it is launched. If our product candidates do not achieve an\plain\cf1\f51\fs20\ql adequate level of acceptance following regulatory approval, if ever, we may not generate significant product revenue and may not\plain\cf1\f51\fs20\ql become profitable.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql We May Expend Our Limited Resources To Pursue A Particular Product Candidate Or Indication And Fail To Capitalize\plain\cf1\f51\fs20\i\ql On Product Candidates Or Indications That May Be More Profitable Or For Which There Is A Greater Likelihood Of Success.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We have limited financial and managerial resources. As a result, we may forego or delay pursuit of opportunities with other\plain\cf1\f51\fs20\ql product candidates or for other indications that later prove to have greater commercial potential. Our resource allocation decisions\plain\cf1\f51\fs20\ql may cause us to fail to timely capitalize on viable commercial products or profitable market opportunities. Our spending on\plain\cf1\f51\fs20\ql current and future research and development programs and product candidates for specific indications may not yield any\plain\cf1\f51\fs20\ql commercially viable products. If we do not accurately evaluate the commercial potential or target market for a particular product\plain\cf1\f51\fs20\ql candidate, we may relinquish valuable rights to that product candidate through collaboration, licensing or other royalty\plain\cf1\f51\fs20\ql arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization\plain\cf1\f51\fs20\ql rights to such product candidate.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql We Face Significant Competition In An Environment Of Rapid Technological Change And The Possibility That Our\plain\cf1\f51\fs20\i\ql Competitors May Achieve Regulatory Approval Before Us Or Develop Therapies That Are More Advanced Or Effective Than\plain\cf1\f51\fs20\i\ql Ours, Which May Harm Our Business And Financial Condition, And Our Ability To Successfully Market Or Commercialize Our\plain\cf1\f51\fs20\i\ql Product Candidates.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql The biotechnology and pharmaceutical industries, including the gene therapy field, are characterized by rapidly changing\plain\cf1\f51\fs20\ql technologies, significant competition and a strong emphasis on intellectual property. We face substantial competition from many\plain\cf1\f51\fs20\ql different sources, including large and specialty pharmaceutical and biotechnology companies, academic research institutions,\plain\cf1\f51\fs20\ql government agencies and public and private research institutions, some or all of which may have greater access to capital or\plain\cf1\f51\fs20\ql resources than we do.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We are aware of several companies focused on developing gene editing in various indications using CRISPR/Cas9 gene\plain\cf1\f51\fs20\ql editing technology, including Intellia Therapeutics, Inc. and Editas Medicine, Inc., or Editas. There can be no certainty that other\plain\cf1\f51\fs20\ql gene editing technologies will not be considered better or more attractive than our technology for the development of products.\plain\cf1\f51\fs20\ql For example, Editas has exclusively licensed a CRISPR system involving a different protein, Cpf1, which can also edit human\plain\cf1\f51\fs20\ql DNA as well as advanced forms of Cas9.\~Editas and certain of its scientific founders have asserted that Cpf1 may work better\plain\cf1\f51\fs20\ql than Cas9 in some cases. Cas9 may be determined to be less attractive than Cpf1 or other CRISPR proteins that have yet to be\plain\cf1\f51\fs20\ql discovered.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql There are additional companies developing therapies using additional gene editing technologies, including transcription\plain\cf1\f51\fs20\ql activator-like effector nucleases (TALENs), meganucleases and zinc finger nucleases (ZFNs). These companies include bluebird\plain\cf1\f51\fs20\ql bio, Cellectis, Poseida Therapeutics, Precision Biosciences, and Sangamo Biosciences. Additional companies developing gene\plain\cf1\f51\fs20\ql therapy products include Abeona Therapeutics, Avalanche Biotechnologies, Dimension Therapeutics, REGENXBIO, Spark\plain\cf1\f51\fs20\ql Therapeutics and uniQure.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In addition to competition from other gene editing therapies or gene therapies, any product we may develop may also face\plain\cf1\f51\fs20\ql competition from other types of therapies, such as small molecule, antibody or protein therapies. In addition, new scientific\plain\cf1\f51\fs20\ql discoveries may cause CRISPR/Cas9 technology, or gene editing as a whole, to be considered an inferior form of therapy.\par\pard\plain\sb264\cf1\f51\fs20\qc 52\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Many of our current or potential competitors, either alone or with their collaboration partners, have significantly greater\plain\cf1\f51\fs20\ql financial resources and expertise in research and development, manufacturing, preclinical studies, conducting clinical trials,\plain\cf1\f51\fs20\ql obtaining regulatory approvals and marketing approved products than we do. Mergers and acquisitions in the pharmaceutical,\plain\cf1\f51\fs20\ql biotechnology, and gene therapy industries may result in even more resources being concentrated among a smaller number of our\plain\cf1\f51\fs20\ql competitors. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative\plain\cf1\f51\fs20\ql arrangements with large and established companies. These competitors also compete with us in recruiting and retaining qualified\plain\cf1\f51\fs20\ql scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in\plain\cf1\f51\fs20\ql acquiring technologies complementary to, or necessary for, our programs. Our commercial opportunity could be reduced or\plain\cf1\f51\fs20\ql eliminated if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe side\plain\cf1\f51\fs20\ql effects, are more convenient, have broader acceptance and higher rates of reimbursement by third party payors or are less\plain\cf1\f51\fs20\ql expensive than any products that we may develop or that would render any products that we may develop obsolete or\plain\cf1\f51\fs20\ql non-competitive. Our competitors also may obtain FDA or other regulatory approval for their products more rapidly than we may\plain\cf1\f51\fs20\ql obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter\plain\cf1\f51\fs20\ql the market. Additionally, technologies developed by our competitors may render our potential product candidates uneconomical or\plain\cf1\f51\fs20\ql obsolete, and we may not be successful in marketing any product candidates we may develop against competitors.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In addition, as a result of the expiration or successful challenge of our patent rights, we could face more litigation with\plain\cf1\f51\fs20\ql respect to the validity and/or scope of patents relating to our competitors\u8217? products and our patents may not be sufficient\plain\cf1\f51\fs20\ql to prevent our competitors from commercializing competing products. The availability of our competitors\u8217? products could\plain\cf1\f51\fs20\ql limit the demand, and the price we are able to charge, for any products that we may develop and commercialize.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql To become and remain profitable, we must develop and eventually commercialize product candidates with significant\plain\cf1\f51\fs20\ql market potential, which will require us to be successful in a range of challenging activities. These activities can include\plain\cf1\f51\fs20\ql completing preclinical studies and clinical trials of our product candidates, obtaining marketing and reimbursement approval for\plain\cf1\f51\fs20\ql these product candidates, manufacturing, marketing and selling those products that are approved and satisfying any post\plain\cf1\f51\fs20\ql marketing requirements. We may never succeed in any or all of these activities and, even if we do, we may never generate\plain\cf1\f51\fs20\ql revenues that are significant or large enough to achieve profitability. If we do achieve profitability, we may not be able to sustain\plain\cf1\f51\fs20\ql or increase profitability on a quarterly or annual basis. Our failure to become and remain profitable would decrease the value of\plain\cf1\f51\fs20\ql our Company and could impair our ability to raise capital, maintain our research and development efforts, expand our business or\plain\cf1\f51\fs20\ql continue our operations. A decline in the value of our Company also could cause shareholders to lose all or part of their\plain\cf1\f51\fs20\ql investment.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Even If We Are Able To Commercialize Any Product Candidates, Such Products May Become Subject To Unfavorable\plain\cf1\f51\fs20\i\ql Pricing Regulations, Third-party Reimbursement Practices, Or Healthcare Reform Initiatives, Which Would Harm Our Business.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql The regulations that govern marketing approvals, pricing, and reimbursement for new biologic products vary widely from\plain\cf1\f51\fs20\ql country to country. Some countries require approval of the sale price of a product before it can be marketed. In many countries,\plain\cf1\f51\fs20\ql the pricing review period begins after marketing or product licensing approval is granted. In some non-U.S. markets, prescription\plain\cf1\f51\fs20\ql pharmaceutical pricing remains subject to continuing governmental control even after initial approval is granted. As a result, we\plain\cf1\f51\fs20\ql might obtain marketing approval for a product in a particular country, but then be subject to price regulations that delay our\plain\cf1\f51\fs20\ql commercial launch of the product, possibly for lengthy time periods, and negatively impact the revenues we are able to generate\plain\cf1\f51\fs20\ql from the sale of the product in that country. Adverse pricing limitations may hinder our ability to recoup our investment in one\plain\cf1\f51\fs20\ql or more product candidates, even if any product candidates we may develop obtain marketing approval.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Our ability to commercialize any products successfully also will depend in part on the extent to which reimbursement for\plain\cf1\f51\fs20\ql these products and related treatments will be available from government health administration authorities, private health insurers,\plain\cf1\f51\fs20\ql and other organizations. Government authorities and third-party payors, such as private health insurers and health maintenance\plain\cf1\f51\fs20\ql organizations, decide which medications they will pay for and establish reimbursement levels. A primary trend in the U.S.\plain\cf1\f51\fs20\ql healthcare industry and elsewhere is cost containment. Government authorities and third-party payors have attempted to control\plain\cf1\f51\fs20\ql costs by limiting coverage and the amount of reimbursement for particular medications. Increasingly, third-party payors are\plain\cf1\f51\fs20\ql requiring that drug companies provide them with predetermined discounts from list prices and are challenging the prices charged\plain\cf1\f51\fs20\ql for medical products. We cannot be sure that reimbursement will be available for any product that we commercialize and, if\plain\cf1\f51\fs20\ql reimbursement is available, the level of reimbursement. Reimbursement may impact the demand for, or the price of, any product\plain\cf1\f51\fs20\ql candidate for which we obtain marketing approval. If reimbursement is not available or is available only to limited levels, we\plain\cf1\f51\fs20\ql may not be able to successfully commercialize any product candidate for which we obtain marketing approval.\par\pard\plain\sb264\cf1\f51\fs20\qc 53\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql There may be significant delays in obtaining reimbursement for newly approved products, and reimbursement coverage may\plain\cf1\f51\fs20\ql be more limited than the purposes for which the product is approved by the FDA or similar regulatory authorities outside the\plain\cf1\f51\fs20\ql United States. Moreover, eligibility for reimbursement does not imply that any product will be paid for in all cases or at a rate\plain\cf1\f51\fs20\ql that covers our costs, including research, development, manufacture, sale, and distribution. Interim reimbursement levels for new\plain\cf1\f51\fs20\ql products, if applicable, may also not be sufficient to cover our costs and may not be made permanent. Reimbursement rates may\plain\cf1\f51\fs20\ql vary according to the use of the product and the clinical setting in which it is used, may be based on reimbursement levels\plain\cf1\f51\fs20\ql already set for lower cost products and may be incorporated into existing payments for other services. Net prices for products\plain\cf1\f51\fs20\ql may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any\plain\cf1\f51\fs20\ql future relaxation of laws that presently restrict imports of products from countries where they may be sold at lower prices than in\plain\cf1\f51\fs20\ql the United States. Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own\plain\cf1\f51\fs20\ql reimbursement policies. Our inability to promptly obtain coverage and profitable payment rates from both government-funded\plain\cf1\f51\fs20\ql and private payors for any approved products we may develop could have a material adverse effect on our operating results, our\plain\cf1\f51\fs20\ql ability to raise capital needed to commercialize products, and our overall financial condition.\par\pard\plain\sb396\cf1\f51\fs20\b\ql Risks Related to Our Relationships with Third Parties\par\pard\plain\sb132\fi528\cf1\f51\fs20\i\ql If Conflicts Arise Between Us And Our Collaborators Or Strategic Partners, These Parties May Act In A Manner Adverse\plain\cf1\f51\fs20\i\ql To Us And Could Limit Our Ability To Implement Our Strategies.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql If conflicts arise between our corporate or academic collaborators or strategic partners and us, the other party may act in a\plain\cf1\f51\fs20\ql manner adverse to us and could limit our ability to implement our strategies. Some of our academic collaborators and strategic\plain\cf1\f51\fs20\ql partners are conducting multiple product development efforts within each area that is the subject of the collaboration with us. Our\plain\cf1\f51\fs20\ql collaborators or strategic partners, however, may develop, either alone or with others, products in related fields that are\plain\cf1\f51\fs20\ql competitive with the products or potential products that are the subject of these collaborations. Competing products, either\plain\cf1\f51\fs20\ql developed by the collaborators or strategic partners or to which the collaborators or strategic partners have rights, may result in\plain\cf1\f51\fs20\ql the withdrawal of partner support for our product candidates.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Some of our collaborators or strategic partners could also become our competitors in the future. Our collaborators or\plain\cf1\f51\fs20\ql strategic partners could develop competing products, preclude us from entering into collaborations with their competitors, fail to\plain\cf1\f51\fs20\ql obtain timely regulatory approvals, terminate their agreements with us prematurely, or fail to devote sufficient resources to the\plain\cf1\f51\fs20\ql development and commercialization of products. Any of these developments could harm our product development efforts.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Our Collaborators Or Strategic Partners May Decide To Adopt Alternative Technologies Or May Be Unable To Develop\plain\cf1\f51\fs20\i\ql Commercially Viable Products With Our Technology, Which Would Negatively Impact Our Revenues And Our Strategy To\plain\cf1\f51\fs20\i\ql Develop These Products.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Our collaborators or strategic partners may adopt alternative technologies, which could decrease the marketability of our\plain\cf1\f51\fs20\ql CRISPR/Cas9 gene editing technology. Additionally, because our current are and we anticipate that any future collaborators or\plain\cf1\f51\fs20\ql strategic partners will be working on more than one development project, they could choose to shift their resources to projects\plain\cf1\f51\fs20\ql other than those they are working on with us. If they do so, this would delay our ability to test our technology and would delay\plain\cf1\f51\fs20\ql or terminate the development of potential products based on our CRISPR/Cas9 gene editing technology. Further, our collaborators\plain\cf1\f51\fs20\ql and strategic partners may elect not to develop products arising out of our collaborative and strategic partnering arrangements or\plain\cf1\f51\fs20\ql to devote sufficient resources to the development, manufacturing, marketing or sale of these products. The failure to develop and\plain\cf1\f51\fs20\ql commercialize a product candidate pursuant to our agreements with our current or future collaborators would prevent us from\plain\cf1\f51\fs20\ql receiving future milestone and royalty payments which would negatively impact our revenues.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Our Collaborators And Strategic Partners May Control Aspects Of Our Clinical Trials and Commercialization Efforts,\plain\cf1\f51\fs20\i\ql Which Could Result In Delays And Other Obstacles In The Commercialization Of Our Proposed Products And Materially Harm\plain\cf1\f51\fs20\i\ql Our Results Of Operations.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql For some programs, we will depend on third party collaborators and strategic partners to design and conduct our clinical\plain\cf1\f51\fs20\ql trials, and for any approved products, the commercialization of such products. As a result, we may not be able to conduct these\plain\cf1\f51\fs20\ql programs in the manner or on the time schedule we currently contemplate, which may negatively impact our business operations.\plain\cf1\f51\fs20\ql In addition, if any of these collaborators or strategic partners withdraw support for our programs or proposed products or\plain\cf1\f51\fs20\ql otherwise impair their development or commercialization, our business could be negatively affected.\~In October 2015, we entered\plain\cf1\f51\fs20\ql into a four-year collaboration agreement with Vertex to research, develop and commercialize new treatments aimed at the\plain\cf1\f51\fs20\ql underlying genetic causes of human diseases, including beta-thalassemia and sickle cell. In December 2017, we entered into the\plain\cf1\f51\fs20\ql JDA with Vertex, initially for the development and commercialization of CTX001 for beta-thalassemia and sickle cell disease. In\plain\cf1\f51\fs20\ql addition, in December 2015, we entered into an agreement with Bayer Healthcare to create a joint venture to discover and\plain\cf1\f51\fs20\ql commercialize therapeutics for the treatment of blood disorders, blindness and heart disease in addition to select indications\plain\cf1\f51\fs20\ql related to other sensory organs, metabolic diseases and autoimmune diseases based on our CRISPR/Cas9 gene editing technology.\par\pard\plain\sb264\cf1\f51\fs20\qc 54\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We and Bayer Healthcare each hold a 50% interest in the joint venture and each have two designees on the management\plain\cf1\f51\fs20\ql board. As such, we cannot control all aspects of the clinical development and commercialization of any product candidate\plain\cf1\f51\fs20\ql developed by the joint venture. Similarly, under our collaboration agreement with Vertex, Vertex has sole authority to select\plain\cf1\f51\fs20\ql genetic targets to pursue and we will not have control over the development of any product candidates for the selected genetic\plain\cf1\f51\fs20\ql targets. Under the JDA, we and Vertex have an equal number of representatives on the various committees contemplated by the\plain\cf1\f51\fs20\ql JDA, which will prevent us from having sole control of the development of CTX001 or any future product candidates subject to\plain\cf1\f51\fs20\ql the JDA. Furthermore, pursuant to the JDA, Vertex will be solely responsible for the commercialization activities of any\plain\cf1\f51\fs20\ql approved products subject to the JDA outside of the United States. Our lack of control over the clinical development and\plain\cf1\f51\fs20\ql commercialization activities in our agreements with Bayer Healthcare and Vertex could cause delays or other difficulties in the\plain\cf1\f51\fs20\ql development and commercialization of product candidates, which may prevent among other things, completion of intended IND\plain\cf1\f51\fs20\ql filings for the first clinical trial for our hemoglobinopathy program targeting sickle cell disease in a timely fashion, if at all, or\plain\cf1\f51\fs20\ql the completion or delay in BLA filings, as well as the timely initiation of clinical trials for beta-thalassemia upon approval of the\plain\cf1\f51\fs20\ql CTA, if at all.\~\~\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In addition, the termination of our agreements with Vertex would prevent us from receiving any milestone, royalty\plain\cf1\f51\fs20\ql payments and other benefits under that agreement. The termination of our joint venture with Bayer Healthcare would prevent us\plain\cf1\f51\fs20\ql from participating in the profits of the joint venture. Either occurrence would have a materially adverse effect on our results of\plain\cf1\f51\fs20\ql operations.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql We May Seek To Establish Additional Collaborations And, If We Are Not Able To Establish Them On Commercially\plain\cf1\f51\fs20\i\ql Reasonable Terms, We May Have To Alter Our Development And Commercialization Plans.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Our product candidate development programs and the potential commercialization of our product candidates will require\plain\cf1\f51\fs20\ql substantial additional cash to fund expenses. For some of our product candidates, we may decide to collaborate with additional\plain\cf1\f51\fs20\ql pharmaceutical and biotechnology companies for the development and potential commercialization of those product candidates.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We face significant competition in seeking appropriate collaborators. Whether we reach a definitive agreement for any\plain\cf1\f51\fs20\ql additional collaborations will depend, among other things, upon our assessment of the collaborator\u8217?s resources and\plain\cf1\f51\fs20\ql expertise, the terms and conditions of the proposed collaboration and the proposed collaborator\u8217?s evaluation of a number\plain\cf1\f51\fs20\ql of factors. Those factors may include the design or results of clinical trials, the likelihood of approval by FDA or similar\plain\cf1\f51\fs20\ql regulatory authorities outside the United States, the potential market for the subject product candidate, the costs and complexities\plain\cf1\f51\fs20\ql of manufacturing and delivering such product candidate to patients, the potential of competing drugs, the existence of uncertainty\plain\cf1\f51\fs20\ql with respect to our ownership of technology, which can exist if there is a challenge to such ownership without regard to the\plain\cf1\f51\fs20\ql merits of the challenge and industry and market conditions generally. The collaborator may also consider alternative product\plain\cf1\f51\fs20\ql candidates or technologies for similar indications that may be available to collaborate on and whether such a collaboration could\plain\cf1\f51\fs20\ql be more attractive than the one with us for our product candidate. The terms of any additional collaborations or other\plain\cf1\f51\fs20\ql arrangements that we may establish may not be favorable to us.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We may also be restricted under existing collaboration agreements from entering into future agreements on certain terms\plain\cf1\f51\fs20\ql with potential collaborators. For example, we have granted exclusive rights to Vertex for certain genetic targets, and during the\plain\cf1\f51\fs20\ql term of the collaboration agreement, we will be restricted from granting rights to other parties to use our CRISPR/Cas9\plain\cf1\f51\fs20\ql technology to pursue therapies that address these genetic targets. Similarly, pursuant to our joint venture agreement with Bayer\plain\cf1\f51\fs20\ql Healthcare, during the term of the joint venture, and for a specified period after the termination of the joint venture, we will be\plain\cf1\f51\fs20\ql prohibited from developing products that use our CRISPR/Cas9 technology in specified fields that would compete with the joint\plain\cf1\f51\fs20\ql venture and Bayer, respectively. The non-competition provisions in each of these agreements could limit our ability to enter into\plain\cf1\f51\fs20\ql strategic collaborations with future collaborators.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We may not be able to negotiate additional collaborations on a timely basis, on acceptable terms, or at all. Collaborations\plain\cf1\f51\fs20\ql are complex and time-consuming to negotiate and document. In addition, there have been a significant number of recent business\plain\cf1\f51\fs20\ql combinations among large pharmaceutical companies that have resulted in a reduced number of potential future collaborators. If\plain\cf1\f51\fs20\ql we are unable to negotiate and enter into new collaborations, we may have to curtail the development of the product candidate\plain\cf1\f51\fs20\ql for which we are seeking to collaborate, reduce or delay its development program or one or more of our other development\plain\cf1\f51\fs20\ql programs, delay its potential commercialization or reduce the scope of any sales or marketing activities, or increase our\plain\cf1\f51\fs20\ql expenditures and undertake development or commercialization activities at our own expense. If we elect to increase our\plain\cf1\f51\fs20\ql expenditures to fund development or commercialization activities on our own, we may need to obtain additional capital, which\plain\cf1\f51\fs20\ql may not be available to us on acceptable terms or at all. If we do not have sufficient funds, we may not be able to further\plain\cf1\f51\fs20\ql develop our product candidates or bring them to market and generate product revenue.\par\pard\plain\sb264\cf1\f51\fs20\qc 55\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql We Expect To Rely On Third Parties To Conduct Our Clinical Trials And Certain Aspects Of Our Preclinical Studies For\plain\cf1\f51\fs20\i\ql Our Product Candidates. If These Third Parties Do Not Successfully Carry Out Their Contractual Duties, Comply With\plain\cf1\f51\fs20\i\ql Regulatory Requirements Or Meet Expected Deadlines, We May Not Be Able To Obtain Regulatory Approval For Or\plain\cf1\f51\fs20\i\ql Commercialize Our Product Candidates And Our Business Could Be Substantially Harmed.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We expect to rely on medical institutions, clinical investigators, contract laboratories and other third parties, such as CROs,\plain\cf1\f51\fs20\ql to conduct future clinical trials and we currently rely on third parties to conduct certain aspects of our preclinical studies for our\plain\cf1\f51\fs20\ql product candidates. Nevertheless, we are responsible for ensuring that each of our preclinical studies and any future clinical trials\plain\cf1\f51\fs20\ql we sponsor are conducted in accordance with the applicable protocol, legal and regulatory requirements and scientific standards\plain\cf1\f51\fs20\ql and our reliance on CROs will not relieve us of our regulatory responsibilities. For example, we will remain responsible for\plain\cf1\f51\fs20\ql ensuring that each of our clinical trials is conducted in accordance with the general investigational plan and protocols for the\plain\cf1\f51\fs20\ql trial. Moreover, the FDA requires us to comply with regulations, commonly referred to as Good Clinical Practices, or GCPs, for\plain\cf1\f51\fs20\ql conducting, recording, and reporting the results of clinical trials to assure that data and reported results are credible and accurate\plain\cf1\f51\fs20\ql and that the rights, integrity, and confidentiality of trial participants are protected. We also are required to register ongoing\plain\cf1\f51\fs20\ql clinical trials and post the results of completed clinical trials on a government-sponsored database, ClinicalTrials.gov, within\plain\cf1\f51\fs20\ql certain timeframes. Failure to do so can result in fines, adverse publicity, and civil and criminal sanctions. For any violations of\plain\cf1\f51\fs20\ql laws and regulations during the conduct of our preclinical studies and clinical trials, we could be subject to warning letters or\plain\cf1\f51\fs20\ql enforcement action that may include civil penalties up to and including criminal prosecution.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We and our CROs will be required to comply with regulations, including GCPs, for conducting, monitoring, recording and\plain\cf1\f51\fs20\ql reporting the results of preclinical studies and clinical trials to ensure that the data and results are scientifically credible and\plain\cf1\f51\fs20\ql accurate and that the trial patients are adequately informed, among other things, of the potential risks of participating in clinical\plain\cf1\f51\fs20\ql trials and their rights are protected. These regulations are enforced by FDA, the Competent Authorities of the Member States of\plain\cf1\f51\fs20\ql the European Economic Area and comparable health regulatory authorities for any drugs in clinical development. The FDA\plain\cf1\f51\fs20\ql enforces GCP regulations through periodic inspections of clinical trial sponsors, principal investigators and trial sites. If we or our\plain\cf1\f51\fs20\ql CROs fail to comply with applicable GCPs, the clinical data generated in our clinical trials may be deemed unreliable and FDA\plain\cf1\f51\fs20\ql or comparable health regulatory authorities may require us to perform additional clinical trials before approving our marketing\plain\cf1\f51\fs20\ql applications. We cannot assure you that, upon inspection, the FDA will determine that any of our future clinical trials will\plain\cf1\f51\fs20\ql comply with GCPs. In addition, our future clinical trials must be conducted with product candidates produced in accordance with\plain\cf1\f51\fs20\ql the requirements in cGMP regulations. Our failure or the failure of our CROs to comply with these regulations may require us to\plain\cf1\f51\fs20\ql repeat clinical trials, which would delay the regulatory approval process and could also subject us to enforcement action.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Although we intend to design the clinical trials for our product candidates, CROs will conduct all of the clinical trials. As a\plain\cf1\f51\fs20\ql result, many important aspects of our development programs, including their conduct and timing, will be outside of our direct\plain\cf1\f51\fs20\ql control. Our reliance on third parties to conduct future preclinical studies and clinical trials will also result in less direct control\plain\cf1\f51\fs20\ql over the management of data developed through preclinical studies and clinical trials than would be the case if we were relying\plain\cf1\f51\fs20\ql entirely upon our own staff. Communicating with outside parties can also be challenging, potentially leading to mistakes as well\plain\cf1\f51\fs20\ql as difficulties in coordinating activities. Outside parties may:
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{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
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{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql form relationships with other entities, some of which may be our competitors.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\sb264\fi528\cf1\f51\fs20\ql These factors may materially adversely affect the willingness or ability of third parties to conduct our preclinical studies\plain\cf1\f51\fs20\ql and clinical trials and may subject us to unexpected cost increases that are beyond our control. If the CROs do not perform\plain\cf1\f51\fs20\ql preclinical studies and future clinical trials in a satisfactory manner, breach their obligations to us or fail to comply with\plain\cf1\f51\fs20\ql regulatory requirements, the development, regulatory approval and commercialization of our product candidates may be delayed,\plain\cf1\f51\fs20\ql we may not be able to obtain regulatory approval and commercialize our product candidates, or our development programs may\plain\cf1\f51\fs20\ql be materially and irreversibly harmed. If we are unable to rely on preclinical and clinical data collected by our CROs, we could\plain\cf1\f51\fs20\ql be required to repeat, extend the duration of, or increase the size of any clinical trials we conduct and this could significantly\plain\cf1\f51\fs20\ql delay commercialization and require significantly greater expenditures.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb264\cf1\f51\fs20\qc 56\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb176\fi528\cf1\f51\fs20\i\ql We Expect To Rely On Third Parties To Manufacture Our Clinical Product Supplies, And We Intend To Rely On Third\plain\cf1\f51\fs20\i\ql Parties For At Least A Portion Of The Manufacturing Process Of Our Product Candidates, If Approved. Our Business Could Be\plain\cf1\f51\fs20\i\ql Harmed If The Third Parties Fail To Provide Us With Sufficient Quantities Of Product Inputs Or Fail To Do So At Acceptable\plain\cf1\f51\fs20\i\ql Quality Levels Or Prices.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We do not currently own any facility that may be used as our clinical-scale manufacturing and processing facility and must\plain\cf1\f51\fs20\ql rely on outside vendors to manufacture supplies and process our product candidates in connection with any clinical trial we\plain\cf1\f51\fs20\ql undertake of such product candidates. We have not yet caused any product candidates to be manufactured or processed on a\plain\cf1\f51\fs20\ql commercial scale and may not be able to do so for any of our product candidates. We will make changes as we work to optimize\plain\cf1\f51\fs20\ql the manufacturing process, and we cannot be sure that even minor changes in the process will result in therapies that are safe and\plain\cf1\f51\fs20\ql effective.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The facilities used by our contract manufacturers to manufacture our product candidates must be approved by the FDA, or\plain\cf1\f51\fs20\ql other health regulatory agencies in other jurisdictions, pursuant to inspections that will be conducted after we submit an\plain\cf1\f51\fs20\ql application to the FDA or other health regulatory agencies. We will not control the manufacturing process of, and will be\plain\cf1\f51\fs20\ql completely dependent on, our contract manufacturing partners for compliance with regulatory requirements, known as cGMP\plain\cf1\f51\fs20\ql requirements, for manufacture of our product candidates. If our contract manufacturers cannot successfully manufacture material\plain\cf1\f51\fs20\ql that conforms to our specifications and the strict regulatory requirements of the FDA or other regulatory authorities, they will not\plain\cf1\f51\fs20\ql be able to secure and/or maintain regulatory approval for their manufacturing facilities. In addition, we have no direct control\plain\cf1\f51\fs20\ql over the ability of our contract manufacturers to maintain adequate quality control, quality assurance and qualified personnel. If\plain\cf1\f51\fs20\ql the FDA or a comparable health regulatory authority does not approve these facilities for the manufacture of our product\plain\cf1\f51\fs20\ql candidates or if it withdraws any such approval in the future, we may need to find alternative manufacturing facilities, which\plain\cf1\f51\fs20\ql would significantly impact our ability to develop, obtain regulatory approval for or market our product candidates, if approved.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Our Relationships With Healthcare Providers, Physicians, And Third-party Payors Will Be Subject To Applicable\plain\cf1\f51\fs20\i\ql Anti-kickback, Fraud And Abuse And Other Healthcare Laws And Regulations, Which Could Expose Us To Criminal Sanctions,\plain\cf1\f51\fs20\i\ql Civil Penalties, Exclusion From Government Healthcare Programs, Contractual Damages, Reputational Harm And Diminished\plain\cf1\f51\fs20\i\ql Profits And Future Earnings.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Although we do not currently have any drugs on the market, once we begin commercializing our product candidates, if\plain\cf1\f51\fs20\ql ever, we will be subject to additional healthcare statutory and regulatory requirements and enforcement by the U.S. federal\plain\cf1\f51\fs20\ql government and states as well as other national, regional or local governments in other jurisdictions in which we conduct our\plain\cf1\f51\fs20\ql business.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Healthcare providers, physicians and third-party payors play a primary role in the recommendation and prescription of any\plain\cf1\f51\fs20\ql product candidates that we may develop for which we obtain marketing approval. Our future arrangements with third-party\plain\cf1\f51\fs20\ql payors and customers may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may\plain\cf1\f51\fs20\ql constrain the business or financial arrangements and relationships through which we market, sell, and distribute our product\plain\cf1\f51\fs20\ql candidates for which we obtain marketing approval. Restrictions under applicable federal and state healthcare laws and\plain\cf1\f51\fs20\ql regulations include the following:
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{\trowd\cellx432\cellx1116\cellx10800\trrh1620
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the federal Anti-Kickback Statute prohibits, among other things, persons from knowingly and willfully soliciting,\plain\intbl\cf1\f51\fs20\ql offering, receiving or providing remuneration, directly or indirectly, in cash or in kind, to induce or reward either\plain\intbl\cf1\f51\fs20\ql the referral of an individual for, or the purchase, order, or recommendation of, any good or service, for which\plain\intbl\cf1\f51\fs20\ql payment may be made under a state or Federal healthcare program, such as Medicare and Medicaid. A person or\plain\intbl\cf1\f51\fs20\ql entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have\plain\intbl\cf1\f51\fs20\ql committed a violation. Violation of the statute may give rise to criminal and/or civil penalties;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh1620\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh2228
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql the federal civil and criminal false claims laws, including the civil False Claims Act, impose criminal and civil\plain\intbl\cf1\f51\fs20\ql penalties, including through civil whistleblower or qui tam actions, against individuals or entities for, among other\plain\intbl\cf1\f51\fs20\ql things, knowingly presenting, or causing to be presented, to the federal government, claims for payment or approval\plain\intbl\cf1\f51\fs20\ql from Medicare, Medicaid, or other government payors that are false, fictitious or fraudulent or knowingly making,\plain\intbl\cf1\f51\fs20\ql using or causing to be made or used a false record or statement to avoid, decrease or conceal an obligation to pay\plain\intbl\cf1\f51\fs20\ql money to the federal government, with potential liability including mandatory treble damages and significant\plain\intbl\cf1\f51\fs20\ql per-claim penalties, currently set at $5,500 to $11,000 per false claim. In addition, the government may assert that\plain\intbl\cf1\f51\fs20\ql a claim including items and services resulting from a violation of the federal Anti-Kickback Statute constitutes a\plain\intbl\cf1\f51\fs20\ql false of fraudulent claim for purposes of the False Claims Act;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh2228\row}}}\pard\plain\sb264\cf1\f51\fs20\qc 57\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
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{\trowd\cellx432\cellx1116\cellx10800\trrh1732
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, as further amended by the\plain\intbl\cf1\f51\fs20\ql Health Information Technology for Economic and Clinical Health Act, or HITECH, and their implementing\plain\intbl\cf1\f51\fs20\ql regulations which impose certain requirements on covered entities, including healthcare providers, health plans and\plain\intbl\cf1\f51\fs20\ql healthcare clearing houses, as well as their business associates that perform certain services with respect to\plain\intbl\cf1\f51\fs20\ql safeguarding the privacy, security and transmission of individually identifiable health information that constitutes\plain\intbl\cf1\f51\fs20\ql protected health information, including mandatory contractual terms and restrictions on the use and/or disclosure of\plain\intbl\cf1\f51\fs20\ql such information without appropriate authorization;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh1732\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh990
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql the federal false statements statute prohibits knowingly and willfully falsifying, concealing, or covering up a\plain\intbl\cf1\f51\fs20\ql material fact or making any materially false statement in connection with the delivery of or payment for healthcare\plain\intbl\cf1\f51\fs20\ql benefits, items, or services; similar to the federal Anti-Kickback Statute, a person or entity does not need to have\plain\intbl\cf1\f51\fs20\ql actual knowledge of the statute or specific intent to violate it in order to have committed a violation;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh990\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh1485
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql the federal physician payment transparency requirements, sometimes referred to as the \u8220?Sunshine Act\u8221?\plain\intbl\cf1\f51\fs20\ql under the Affordable Care Act, require manufacturers of drugs, devices, biologics and medical supplies that are\plain\intbl\cf1\f51\fs20\ql reimbursable under Medicare, Medicaid, or the Children\u8217?s Health Insurance Program to report to the\plain\intbl\cf1\f51\fs20\ql Department of Health and Human Services information related to physician payments and other transfers of value to\plain\intbl\cf1\f51\fs20\ql physicians and teaching hospitals, and ownership and investment interests held by physicians and other healthcare\plain\intbl\cf1\f51\fs20\ql providers and their immediate family members and applicable group purchasing organizations; and\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh1485\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh742
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql analogous laws and regulations in U.S. states, and in other countries, regions or localities in which we may do\plain\intbl\cf1\f51\fs20\ql business, such as state anti-kickback and false claims laws, which may apply to healthcare items or services that\plain\intbl\cf1\f51\fs20\ql are reimbursed by non-governmental third-party payors, including private insurers.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh742\row}}}\pard\plain\sb264\fi528\cf1\f51\fs20\ql Because of the breadth of these laws and the narrowness of the statutory exceptions and safe harbors available, it is\plain\cf1\f51\fs20\ql possible that some of our business activities could be subject to challenge under one or more of such laws. If our operations are\plain\cf1\f51\fs20\ql found to be in violation of any of the laws described above or any other government regulations that apply to us, we may be\plain\cf1\f51\fs20\ql subject to penalties, including civil and criminal penalties, damages, fines, exclusion from participation in government health care\plain\cf1\f51\fs20\ql programs, such as Medicare and Medicaid, imprisonment, and the curtailment or restructuring of our operations, any of which\plain\cf1\f51\fs20\ql could adversely affect our business, financial condition, results of operations, and prospects.{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The provision of benefits or advantages to physicians to induce or encourage the prescription, recommendation,\plain\cf1\f51\fs20\ql endorsement, purchase, supply, order, or use of medicinal products is prohibited in the European Union. The provision of benefits\plain\cf1\f51\fs20\ql or advantages to physicians is also governed by the national anti-bribery laws of European Union Member States, such as the\plain\cf1\f51\fs20\ql UK Bribery Act 2010. Infringement of these laws could result in substantial fines and imprisonment.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Payments made to physicians in certain European Union Member States must be publicly disclosed. Moreover, agreements\plain\cf1\f51\fs20\ql with physicians often must be the subject of prior notification and approval by the physician\u8217?s employer, his or her\plain\cf1\f51\fs20\ql competent professional organization, and/or the regulatory authorities of the individual European Union Member States. These\plain\cf1\f51\fs20\ql requirements are provided in the national laws, industry codes, or professional codes of conduct applicable in the European Union\plain\cf1\f51\fs20\ql Member States. Failure to comply with these requirements could result in reputational risk, public reprimands, administrative\plain\cf1\f51\fs20\ql penalties, fines, or imprisonment.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Efforts to ensure that our business arrangements with third parties will comply with applicable healthcare laws and\plain\cf1\f51\fs20\ql regulations will involve substantial costs. It is possible that governmental authorities will conclude that our business practices\plain\cf1\f51\fs20\ql may not comply with current or future statutes, regulations, or case law involving applicable fraud and abuse or other healthcare\plain\cf1\f51\fs20\ql laws and regulations. If our operations, including activities that may be conducted by sales and marketing team we establish, are\plain\cf1\f51\fs20\ql found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to\plain\cf1\f51\fs20\ql significant civil, criminal, and administrative penalties, damages, fines, exclusion from government funded healthcare programs,\plain\cf1\f51\fs20\ql such as Medicare and Medicaid, and the curtailment or restructuring of our operations. If any of the physicians or other providers\plain\cf1\f51\fs20\ql or entities with whom we expect to do business is found to be not in compliance with applicable laws, they may be subject to\plain\cf1\f51\fs20\ql criminal, civil, or administrative sanctions, including exclusions from government funded healthcare programs. Liabilities they\plain\cf1\f51\fs20\ql incur pursuant to these laws could result in significant costs or an interruption in operations, which could have a material adverse\plain\cf1\f51\fs20\ql effect on our business, financial condition, results of operations, and prospects.\par\pard\plain\sb264\cf1\f51\fs20\qc 58\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb396\cf1\f51\fs20\b\ql Risks Related to Employee Matters, Managing Growth and Other Risks Related to Our Business\par\pard\plain\sb132\fi528\cf1\f51\fs20\i\ql Our Future Success Depends On Our Ability To Retain Key Executives And To Attract, Retain And Motivate Qualified\plain\cf1\f51\fs20\i\ql Personnel.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We are highly dependent on the research and development, clinical, commercial and business development expertise of\plain\cf1\f51\fs20\ql Dr.\~Samarth Kulkarni, our Chief Executive Officer, as well as the other principal members of our management, scientific and\plain\cf1\f51\fs20\ql clinical team. Although we have entered into employment agreements with our executive officers, each of them may terminate\plain\cf1\f51\fs20\ql their employment with us at any time. We do not maintain \u8220?key person\u8221? insurance for any of our executives or\plain\cf1\f51\fs20\ql other employees. In addition, we rely on consultants and advisors, including scientific and clinical advisors, to assist us in\plain\cf1\f51\fs20\ql formulating our research and development and commercialization strategy. Our consultants and advisors may be employed by\plain\cf1\f51\fs20\ql employers other than us and may have commitments under consulting or advisory contracts with other entities that may limit\plain\cf1\f51\fs20\ql their availability to us. The loss of the services of our executive officers or other key employees or consultants could impede the\plain\cf1\f51\fs20\ql achievement of our research, development and commercialization objectives and seriously harm our ability to successfully\plain\cf1\f51\fs20\ql implement our business strategy. For example, since our IPO our former Chief Executive Officer resigned in his role as Chief\plain\cf1\f51\fs20\ql Executive Officer and became our President and Chairman of the Board of Directors, and our former Chief Financial Officer\plain\cf1\f51\fs20\ql resigned. While we have promoted Samarth Kulkarni as our new Chief Executive Officer and hired Michael Tomsicek as our\plain\cf1\f51\fs20\ql new Chief Financial Officer, there is no assurance that we will be able to find qualified replacements in a timely manner, if at\plain\cf1\f51\fs20\ql all, in the event of the departure of other executive officers or key employees. If we are unable to retain high quality personnel,\plain\cf1\f51\fs20\ql our ability to pursue our growth strategy will be limited.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We will also need to recruit and retain qualified scientific, clinical and commercial personnel as we advance the\plain\cf1\f51\fs20\ql development of our product candidates and product pipeline. We may be unable to hire, train, retain or motivate these key\plain\cf1\f51\fs20\ql personnel on acceptable terms given the competition among numerous pharmaceutical and biotechnology companies for similar\plain\cf1\f51\fs20\ql personnel. We also experience competition for the hiring of scientific, clinical and commercial personnel from universities and\plain\cf1\f51\fs20\ql research institutions. Failure to succeed in clinical trials may make it more challenging to recruit and retain qualified scientific\plain\cf1\f51\fs20\ql personnel.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In addition, being domiciled and organized in Switzerland may restrict our ability to attract, motivate and retain the\plain\cf1\f51\fs20\ql required level of qualified personnel. In Switzerland, in 2013 legislation was adopted affecting compensation payable by public\plain\cf1\f51\fs20\ql companies to members of its board of directors and executive team.\~Among other things, such legislation (i)\~imposes an annual\plain\cf1\f51\fs20\ql binding shareholders\u8217? \u8220?say on pay\u8221? vote with respect to the compensation of executive management,\plain\cf1\f51\fs20\ql including executive officers and the board of directors; (ii)\~prohibits severance, advances, transaction premiums and similar\plain\cf1\f51\fs20\ql payments to executive officers and directors; and (iii)\~requires companies to specify various compensation-related matters in their\plain\cf1\f51\fs20\ql articles of association, thus requiring them to be approved by a shareholders\u8217? vote.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql We Will Need To Develop And Expand Our Company, And We May Encounter Difficulties In Managing This Development\plain\cf1\f51\fs20\i\ql And Expansion, Which Could Disrupt Our Operations.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql As of December 31, 2017, we had 127 full-time employees and we expect to increase our number of employees and the\plain\cf1\f51\fs20\ql scope of our operations in 2018 and beyond as we conduct activities as a public company and seek to advance development and\plain\cf1\f51\fs20\ql if successful, commercialization, of our product candidates. To manage our anticipated development and expansion, we must\plain\cf1\f51\fs20\ql continue to implement and improve our managerial, operational and financial systems, expand our facilities and continue to\plain\cf1\f51\fs20\ql recruit and train additional qualified personnel. Also, our management may need to divert a disproportionate amount of its\plain\cf1\f51\fs20\ql attention away from its day-to-day activities and devote a substantial amount of time to managing these expansion activities.\plain\cf1\f51\fs20\ql Due to our limited resources, we may not be able to effectively manage the expansion of our operations or recruit and train\plain\cf1\f51\fs20\ql additional qualified personnel. This may result in weaknesses in our infrastructure, give rise to operational mistakes, loss of\plain\cf1\f51\fs20\ql business opportunities, loss of employees and reduced productivity among remaining employees. The physical expansion of our\plain\cf1\f51\fs20\ql operations may lead to significant costs and may divert financial resources from other projects, such as the development of our\plain\cf1\f51\fs20\ql product candidates. If our management is unable to effectively manage our expected expansion, our expenses may increase more\plain\cf1\f51\fs20\ql than expected, our ability to generate or increase our revenue could be reduced and we may not be able to implement our\plain\cf1\f51\fs20\ql business strategy. Our future financial performance and our ability to commercialize our product candidates, if approved, and\plain\cf1\f51\fs20\ql compete effectively will depend, in part, on our ability to effectively manage the future development and expansion of our\plain\cf1\f51\fs20\ql company.\par\pard\plain\sb264\cf1\f51\fs20\qc 59\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Our Employees, Principal Investigators, Consultants And Commercial Partners May Engage In Misconduct Or Other\plain\cf1\f51\fs20\i\ql Improper Activities, Including Non-compliance With Regulatory Standards And Requirements And Insider Trading.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We are exposed to the risk of fraud or other misconduct by our employees, consultants, and commercial partners, and, if\plain\cf1\f51\fs20\ql we commence clinical trials, our principal investigators. Misconduct by these parties could include intentional failures to comply\plain\cf1\f51\fs20\ql with FDA regulations or the regulations applicable in the European Union and other jurisdictions, provide accurate information to\plain\cf1\f51\fs20\ql the FDA, the European Commission, and other regulatory authorities, comply with healthcare fraud and abuse laws and\plain\cf1\f51\fs20\ql regulations in the United States and in other jurisdictions, report financial information or data accurately or disclose unauthorized\plain\cf1\f51\fs20\ql activities to us. In particular, sales, marketing and business arrangements in the healthcare industry are subject to extensive laws\plain\cf1\f51\fs20\ql and regulations intended to prevent fraud, misconduct, kickbacks, self-dealing and other abusive practices. These laws and\plain\cf1\f51\fs20\ql regulations restrict or prohibit a wide range of pricing, discounting, marketing and promotion, sales commission, customer\plain\cf1\f51\fs20\ql incentive programs, and other business arrangements. Such misconduct also could involve the improper use of information\plain\cf1\f51\fs20\ql obtained in the course of clinical trials or interactions with the FDA or other regulatory authorities, which could result in\plain\cf1\f51\fs20\ql regulatory sanctions and cause serious harm to our reputation. We have adopted a code of conduct applicable to all of our\plain\cf1\f51\fs20\ql employees, but it is not always possible to identify and deter employee misconduct, and the precautions we take to detect and\plain\cf1\f51\fs20\ql prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from\plain\cf1\f51\fs20\ql government investigations or other actions or lawsuits stemming from a failure to comply with these laws or regulations.\plain\cf1\f51\fs20\ql Additionally, we are subject to the risk that a person could allege such fraud or other misconduct, even if none occurred. If any\plain\cf1\f51\fs20\ql such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could\plain\cf1\f51\fs20\ql have a significant impact on our business, financial condition, results of operations, and prospects, including the imposition of\plain\cf1\f51\fs20\ql civil, criminal and administrative penalties, damages, monetary fines, possible exclusion from participation in Medicare, Medicaid\plain\cf1\f51\fs20\ql and other federal healthcare programs, contractual damages, reputational harm, diminished profits and future earnings and\plain\cf1\f51\fs20\ql curtailment of our operations, any of which could adversely affect our ability to operate our business and our results of\plain\cf1\f51\fs20\ql operations.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql If We Fail To Comply With Environmental, Health And Safety Laws And Regulations, We Could Become Subject To Fines\plain\cf1\f51\fs20\i\ql Or Penalties Or Incur Costs That Could Harm Our Business.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We are subject to numerous environmental, health and safety laws and regulations, including those governing laboratory\plain\cf1\f51\fs20\ql procedures and the handling, use, storage, treatment and disposal of hazardous materials and wastes. Our operations involve the\plain\cf1\f51\fs20\ql use of hazardous and flammable materials, including chemicals and biological materials. Our operations also produce hazardous\plain\cf1\f51\fs20\ql waste products. We contract with third parties for the disposal of these materials and wastes. We will not be able to eliminate the\plain\cf1\f51\fs20\ql risk of contamination or injury from these materials. In the event of contamination or injury resulting from any use by us of\plain\cf1\f51\fs20\ql hazardous materials, we could be held liable for any resulting damages, and any liability could exceed our resources. We also\plain\cf1\f51\fs20\ql could incur significant costs associated with civil or criminal fines and penalties for failure to comply with such laws and\plain\cf1\f51\fs20\ql regulations.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Although we anticipate obtaining product liability insurance coverage in advance of the commencement of any clinical trial\plain\cf1\f51\fs20\ql of our product candidates, it may not be adequate to cover all liabilities that we may incur. Further, we anticipate that we will\plain\cf1\f51\fs20\ql need to increase our insurance coverage if we successfully commercialize any product candidate. Insurance coverage is\plain\cf1\f51\fs20\ql increasingly expensive. We may not be able to maintain insurance coverage at a reasonable cost or in an amount adequate to\plain\cf1\f51\fs20\ql satisfy any liability that may arise.{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In addition, we may incur substantial costs in order to comply with current or future environmental, health and safety laws\plain\cf1\f51\fs20\ql and regulations. These current or future laws and regulations may impair our research, development or production efforts. Our\plain\cf1\f51\fs20\ql failure to comply with these laws and regulations also may result in substantial fines, penalties or other sanctions.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Product Liability Lawsuits Against Us Could Cause Us To Incur Substantial Liabilities And Could Limit Commercialization\plain\cf1\f51\fs20\i\ql Of Any Product Candidates That We May Develop.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We will face an inherent risk of product liability exposure related to the testing of our product candidates in human clinical\plain\cf1\f51\fs20\ql trials and will face an even greater risk if we commercially sell any product candidates that we may develop. If we cannot\plain\cf1\f51\fs20\ql successfully defend ourselves against claims that our product candidates caused injuries, we could incur substantial liabilities.\plain\cf1\f51\fs20\ql Regardless of merit or eventual outcome, liability claims may result in:
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{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
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{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql withdrawal of clinical trial participants;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
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{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
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{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
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{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\sb264\cf1\f51\fs20\qc 60\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql the inability to commercialize any product candidates that we may develop.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\sb264\fi528\cf1\f51\fs20\ql Although we anticipate obtaining product liability insurance coverage in advance of the commencement of any clinical trial\plain\cf1\f51\fs20\ql of our product candidates, it may not be adequate to cover all liabilities that we may incur.\~Further, we anticipate that we will\plain\cf1\f51\fs20\ql need to increase our insurance coverage if we successfully commercialize any product candidate. Insurance coverage is\plain\cf1\f51\fs20\ql increasingly expensive. We may not be able to maintain insurance coverage at a reasonable cost or in an amount adequate to\plain\cf1\f51\fs20\ql satisfy any liability that may arise.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql If We Fail To Establish And Maintain Proper And Effective Internal Control Over Financial Reporting, Our Operating\plain\cf1\f51\fs20\i\ql Results And Our Ability To Operate Our Business Could Be Harmed.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Ensuring that we have adequate internal financial and accounting controls and procedures in place so that we can produce\plain\cf1\f51\fs20\ql accurate financial statements on a timely basis is a costly and time-consuming effort that needs to be re-evaluated frequently.\plain\cf1\f51\fs20\ql Our internal control over financial reporting is a process designed to provide reasonable assurance regarding the reliability of\plain\cf1\f51\fs20\ql financial reporting and the preparation of financial statements in accordance with generally accepted accounting principles. We\plain\cf1\f51\fs20\ql have designed our disclosure controls and procedures to reasonably assure that information we must disclose in reports we file or\plain\cf1\f51\fs20\ql submit under the Exchange Act is accumulated and communicated to management, and recorded, processed, summarized and\plain\cf1\f51\fs20\ql reported within the time periods specified in the rules and forms of the SEC. We believe that any disclosure controls and\plain\cf1\f51\fs20\ql procedures or internal controls and procedures, no matter how well-conceived and operated, can provide only reasonable, not\plain\cf1\f51\fs20\ql absolute, assurance that the objectives of the control system are met. These inherent limitations include the realities that\plain\cf1\f51\fs20\ql judgments in decision-making can be faulty, and that breakdowns can occur because of simple error or mistake. Additionally,\plain\cf1\f51\fs20\ql controls can be circumvented by the individual acts of some persons, by collusion of two or more people or by an unauthorized\plain\cf1\f51\fs20\ql override of the controls. Accordingly, because of the inherent limitations in our control system, misstatements due to error or\plain\cf1\f51\fs20\ql fraud may occur and not be detected.\~\~\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Our Internal Computer Systems, Or Those Of Our Collaborators Or Other Contractors Or Consultants, May Fail Or Suffer\plain\cf1\f51\fs20\i\ql Security Breaches, Which Could Result In A Material Disruption Of Our Product Development Programs.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Our internal computer systems and those of our current and any future collaborators and other contractors or consultants are\plain\cf1\f51\fs20\ql vulnerable to damage from computer viruses, unauthorized access, natural disasters, terrorism, war and telecommunication and\plain\cf1\f51\fs20\ql electrical failures. While we have not experienced any such material system failure, accident or security breach to date, if such an\plain\cf1\f51\fs20\ql event were to occur and cause interruptions in our operations, it could result in a disruption of our development programs and\plain\cf1\f51\fs20\ql our business operations, whether due to a loss of our trade secrets or other proprietary information or other similar disruptions.\plain\cf1\f51\fs20\ql For example, the loss of clinical trial data from future clinical trials could result in delays in our regulatory approval efforts and\plain\cf1\f51\fs20\ql significantly increase our costs to recover or reproduce the data. To the extent that any disruption or security breach were to\plain\cf1\f51\fs20\ql result in a loss of, or damage to, our data or applications, or inappropriate disclosure of confidential or proprietary information,\plain\cf1\f51\fs20\ql we could incur liability, our competitive position could be harmed and the further development and commercialization of our\plain\cf1\f51\fs20\ql product candidates could be delayed.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Our Business Is Subject To Economic, Political, Regulatory And Other Risks Associated With International Operations.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Our business is subject to risks associated with conducting business internationally. We and a number of our suppliers and\plain\cf1\f51\fs20\ql collaborative and clinical study relationships are located outside the United States. Accordingly, our future results could be\plain\cf1\f51\fs20\ql harmed by a variety of factors, including:
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{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql differing regulatory requirements for drug approvals in non-U.S. countries;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
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{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
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{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
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{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
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{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh0\row}}}\pard\plain\sb264\cf1\f51\fs20\qc 61\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
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{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh495
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql compliance with tax, employment, immigration and labor laws for employees living or traveling outside the United\plain\intbl\cf1\f51\fs20\ql States;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh495\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
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{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
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{\trowd\cellx432\cellx1116\cellx10800\trrh495\row}}}\pard\plain\cf1\f51\fs12\ql \~
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\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql business interruptions resulting from geo-political actions, including war and terrorism, or natural disasters\plain\intbl\cf1\f51\fs20\ql including floods and fires; and\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh495\row}}}
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\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql adverse effects and instability in global financial markets, political institutions and regulatory agencies resulting\plain\intbl\cf1\f51\fs20\ql from the United Kingdom\u8217?s June 23, 2016 vote to leave the European Union and subsequent invocation of\plain\intbl\cf1\f51\fs20\ql Article 50 of the Lisbon Treaty on March 29, 2017.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh742\row}}}\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Our Business Operations Have a Substantial International Footprint and We May Further Expand In The Future, Which\plain\cf1\f51\fs20\i\ql Presents Challenges In Managing Our Business Operations.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We are headquartered in Zug, Switzerland and have offices in the U.S. and the United Kingdom. In addition, we may\plain\cf1\f51\fs20\ql expand our international operations into other countries in the future. While we have acquired significant management and other\plain\cf1\f51\fs20\ql personnel with substantial experience, conducting our business in multiple countries subjects us to a variety of risks and\plain\cf1\f51\fs20\ql complexities that may materially and adversely affect our business, results of operations, financial condition and growth\plain\cf1\f51\fs20\ql prospects, including, among other things:
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{\trowd\cellx432\cellx1116\cellx10800\trrh495
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{\trowd\cellx432\cellx1116\cellx10800\trrh495\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql country-specific tax, labor and employment laws and regulations;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh495
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql challenges inherent in efficiently managing employees in diverse geographies, including the need to adapt systems,\plain\intbl\cf1\f51\fs20\ql policies, benefits and compliance programs to differing labor and other regulations;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh495\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql liabilities for activities of, or related to, our international operations or product candidates;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql changes in currency rates; and\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql regulations relating to data security and the unauthorized use of, or access to, commercial and personal information.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\pard\plain\sb264\fi528\cf1\f51\fs20\ql As we continue to expand our operations, our corporate structure and tax structure has become substantially more complex.\plain\cf1\f51\fs20\ql In connection with our current and future potential partnerships, we are actively engaged in developing and applying technologies\plain\cf1\f51\fs20\ql and intellectual property with a view toward commercialization of products globally, often with commercialization partners. In\plain\cf1\f51\fs20\ql connection with those activities, we already have and will likely continue to engage in complex cross-border and global\plain\cf1\f51\fs20\ql transactions involving our technology, intellectual property and other assets, between CRISPR and other entities such as partners\plain\cf1\f51\fs20\ql and licensees, and between companies within the CRISPR group. Such cross-border and global arrangements are both difficult to\plain\cf1\f51\fs20\ql manage and can potentially give rise to complexities in areas such as tax treatment, particularly since we are subject to multiple\plain\cf1\f51\fs20\ql tax regimes and different tax authorities can also take different views from each other, even as regards the same cross-border\plain\cf1\f51\fs20\ql transaction or arrangement. There can be no assurance that we will effectively manage this increased complexity without\plain\cf1\f51\fs20\ql experiencing operating inefficiencies, control deficiencies or tax liabilities. Significant management time and effort is required to\plain\cf1\f51\fs20\ql effectively manage the increased complexity of our company, and our failure to successfully do so could have a material adverse\plain\cf1\f51\fs20\ql effect on our business, financial condition, results of operations and growth prospects.\par\pard\plain\sb264\cf1\f51\fs20\qc 62\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb396\cf1\f51\fs20\b\ql Risks Related to Intellectual Property\par\pard\plain\sb132\fi528\cf1\f51\fs20\i\ql If We Are Unable To Adequately Protect Our Proprietary Technology Or Obtain And Maintain Patent Protection For The\plain\cf1\f51\fs20\i\ql Products We Develop And For Our Technology And Product Candidates, Or If The Scope Of The Patent Protection Obtained Is\plain\cf1\f51\fs20\i\ql Not Sufficiently Broad, Our Competitors Could Develop And Commercialize Products And Technology Similar Or Identical To\plain\cf1\f51\fs20\i\ql Ours, And Our Ability To Successfully Commercialize Any Product Candidates We May Develop, And Our Technology May Be\plain\cf1\f51\fs20\i\ql Adversely Affected.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Our success depends in large part on our ability to obtain and maintain proprietary or intellectual property protection in the\plain\cf1\f51\fs20\ql United States and other countries with respect to our CRISPR/Cas9 platform technology and any proprietary product candidates\plain\cf1\f51\fs20\ql and technology we develop. Currently, no patents covering our CRISPR/Cas9 platform or product candidates have been issued to\plain\cf1\f51\fs20\ql us in the United States and one of the patent applications we have licensed that may cover our platform was the subject of an\plain\cf1\f51\fs20\ql interference proceeding at the United States Patent and Trademark Office, or USPTO; the termination of the interference\plain\cf1\f51\fs20\ql proceeding has been appealed to the U.S. Court of Appeals for the Federal Circuit, or Federal Circuit, as discussed below. One\plain\cf1\f51\fs20\ql patent covering our CRISPR/Cas9 platform was issued in Europe, but is the subject of opposition proceedings. We seek to\plain\cf1\f51\fs20\ql protect our proprietary position by in-licensing intellectual property to cover our platform technology and filing patent\plain\cf1\f51\fs20\ql applications in the United States and in other jurisdictions related to our technologies and product candidates that are important to\plain\cf1\f51\fs20\ql our business. We also rely on trade secrets, know-how and continuing technological innovation to develop and maintain our\plain\cf1\f51\fs20\ql proprietary and intellectual property position. If we or our licensors are unable to obtain or maintain patent protection with\plain\cf1\f51\fs20\ql respect to our CRISPR/Cas9 platform technology and any proprietary products and technology we develop, our business, financial\plain\cf1\f51\fs20\ql condition, results of operations and prospects could be materially harmed.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The scope of patent protection that will be available to us in the United States and in other countries is uncertain. Changes\plain\cf1\f51\fs20\ql in either the patent laws or their interpretation in the United States and other countries may diminish our ability to protect our\plain\cf1\f51\fs20\ql inventions, obtain, maintain and enforce our intellectual property rights and, more generally, could affect the value of our\plain\cf1\f51\fs20\ql intellectual property or narrow the scope of our owned and licensed patents. With respect to both in-licensed and owned\plain\cf1\f51\fs20\ql intellectual property, we cannot predict whether the patent applications we and our licensors are currently pursuing will issue as\plain\cf1\f51\fs20\ql patents in any particular jurisdiction or whether the claims of any issued patents will provide sufficient protection from\plain\cf1\f51\fs20\ql competitors, or if any such patents will be found invalid, unenforceable or not infringed if challenged by our competitors.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The patent prosecution process is expensive, time-consuming, and complex, and we may not be able to file, prosecute,\plain\cf1\f51\fs20\ql maintain, enforce, or license all necessary or desirable patent applications at a reasonable cost or in a timely manner. It is also\plain\cf1\f51\fs20\ql possible that we will fail to identify patentable aspects of our research and development output in time to obtain patent\plain\cf1\f51\fs20\ql protection. Although we enter into non-disclosure and confidentiality agreements with parties who have access to confidential or\plain\cf1\f51\fs20\ql patentable aspects of our research and development output, such as our employees, corporate collaborators, outside scientific\plain\cf1\f51\fs20\ql collaborators, CROs, contract manufacturers, consultants advisors, and other third parties, any of these parties may breach the\plain\cf1\f51\fs20\ql agreements and disclose such output before a patent application is filed, thereby jeopardizing our ability to seek patent protection.\plain\cf1\f51\fs20\ql In addition, publications of discoveries in the scientific literature often lag behind the actual discoveries and patent applications in\plain\cf1\f51\fs20\ql the United States and other jurisdictions are typically not published until 18\~months after filing, or in some cases not at all.\plain\cf1\f51\fs20\ql Therefore, we cannot know with any degree of certainty whether the inventors of our licensed patents and applications were the\plain\cf1\f51\fs20\ql first to make the inventions claimed in our owned or any licensed patents or pending patent applications, or that we were the first\plain\cf1\f51\fs20\ql to file for patent protection of such inventions.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The patent position of biotechnology and pharmaceutical companies generally is highly uncertain, involves complex legal\plain\cf1\f51\fs20\ql and factual questions, and has been the subject of much litigation in recent years. As a result, the issuance, scope, validity,\plain\cf1\f51\fs20\ql enforceability, and commercial value of our patent rights are highly uncertain. Our pending and future patent applications may\plain\cf1\f51\fs20\ql not result in patents being issued which protect our technology or product candidates or which effectively prevent others from\plain\cf1\f51\fs20\ql commercializing competitive technologies and product candidates.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Moreover, the coverage claimed in a patent application can be significantly reduced before the patent is issued, and its\plain\cf1\f51\fs20\ql scope can be reinterpreted after issuance. Even if patent applications we license or own currently or in the future issue as patents,\plain\cf1\f51\fs20\ql they may not issue in a form that will provide us with any meaningful protection, prevent competitors or other third parties from\plain\cf1\f51\fs20\ql competing with us, or otherwise provide us with any competitive advantage. Any patents that we hold or in-license may be\plain\cf1\f51\fs20\ql challenged, narrowed, circumvented, or invalidated by third parties. Consequently, we do not know whether any of our platform\plain\cf1\f51\fs20\ql advances and product candidates will be protectable or remain protected by valid and enforceable patents. Our competitors or\plain\cf1\f51\fs20\ql other third parties may be able to circumvent our patents by developing similar or alternative technologies or products in a\plain\cf1\f51\fs20\ql non-infringing manner. For example, we are aware that third parties have suggested the use of the CRISPR technology in\plain\cf1\f51\fs20\ql conjunction with a protein other than Cas9. Our owned and in-licensed patents may not cover such technology. If our\plain\cf1\f51\fs20\ql competitors commercialize the CRISPR technology in conjunction with a protein other than Cas9, our business, financial\plain\cf1\f51\fs20\ql condition, results of operations, and prospects could be materially adversely affected.\par\pard\plain\sb264\cf1\f51\fs20\qc 63\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The issuance of a patent is not conclusive as to its inventorship, scope, validity or enforceability and our patents may be\plain\cf1\f51\fs20\ql challenged in the courts or patent offices in the United States and in other jurisdictions. We may be subject to a third party\plain\cf1\f51\fs20\ql preissuance submission of prior art to the USPTO, or a patent office in another jurisdiction, or become involved in opposition,\plain\cf1\f51\fs20\ql derivation, revocation, reexamination, post-grant review and inter partes review, or interference proceedings, or litigation\plain\cf1\f51\fs20\ql challenging our patent rights or the patent rights of others. Indeed, certain of our fundamental intellectual property has been\plain\cf1\f51\fs20\ql subject to third party observations outside the United States and interference proceedings within the United States. Competitors\plain\cf1\f51\fs20\ql may claim that they invented the inventions claimed in such issued patents or patent applications prior to our inventors, or may\plain\cf1\f51\fs20\ql have filed patent applications before our inventors did. A competitor may also claim that our products and services infringe its\plain\cf1\f51\fs20\ql patents and that we therefore cannot practice our technology as claimed under our patent applications, if issued. An adverse\plain\cf1\f51\fs20\ql determination in any such claim may result in our inability to manufacture or commercialize products without infringing\plain\cf1\f51\fs20\ql third-party patent rights. Competitors may also contest our patents, if issued, by showing that the invention was not\plain\cf1\f51\fs20\ql patent-eligible, was not novel, was obvious or that the patent claims failed any other requirement for patentability. An adverse\plain\cf1\f51\fs20\ql determination in any such submission, proceeding or litigation could reduce the scope of, or invalidate, our patent rights or allow\plain\cf1\f51\fs20\ql third parties to commercialize our technology or products and compete directly with us, without payment to us. Moreover, we, or\plain\cf1\f51\fs20\ql one of our licensors, may have to participate in additional interference proceedings declared by the USPTO to determine priority\plain\cf1\f51\fs20\ql of invention or in post-grant challenge proceedings, such as oppositions in a non-U.S. patent office, that challenge priority of\plain\cf1\f51\fs20\ql invention or other features of patentability. Such challenges may result in loss of patent rights, loss of exclusivity or freedom to\plain\cf1\f51\fs20\ql operate, or in patent claims being narrowed, invalidated or held unenforceable, in whole or in part, which could limit our ability\plain\cf1\f51\fs20\ql to stop others from using or commercializing similar or identical technology and products, or limit the duration of the patent\plain\cf1\f51\fs20\ql protection of our technology and product candidates. Such proceedings also may result in substantial cost and require significant\plain\cf1\f51\fs20\ql time from our scientists and management, even if the eventual outcome is favorable to us. In addition, if the breadth or strength\plain\cf1\f51\fs20\ql of protection provided by our patents and patent applications is threatened, it could dissuade companies from collaborating with\plain\cf1\f51\fs20\ql us to license, develop or commercialize current or future product candidates.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql We Are Required To Pay Royalties Under Our License Agreements With Third-Party Licensors, And We Must Use\plain\cf1\f51\fs20\i\ql Commercially Reasonable Diligence Efforts And Meet Milestones To Maintain Our License Rights.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Under our in-license agreements, including our in-license agreements with Dr. Emmanuelle Charpentier, we will be\plain\cf1\f51\fs20\ql required to pay royalties based on our revenues from sales of our products utilizing the licensed technologies and these royalty\plain\cf1\f51\fs20\ql payments could adversely affect the overall profitability for us of any products that we may seek to commercialize. Under each\plain\cf1\f51\fs20\ql of our in-license agreements with, Dr. Charpentier, we have an obligation to use commercially reasonable efforts to develop and\plain\cf1\f51\fs20\ql obtain regulatory approval to market a licensed therapeutic product. Our in-license agreements with Dr. Charpentier also include\plain\cf1\f51\fs20\ql an obligation to file a U.S. Investigational New Drug application (or its equivalent in a major market country) by April 2021 and\plain\cf1\f51\fs20\ql an obligation to file a U.S. Investigational New Drug application (or its equivalent in a major market country) by April 2024. We\plain\cf1\f51\fs20\ql may not be successful in meeting these obligations in the future on a timely basis or at all. Our failure to meet these obligations\plain\cf1\f51\fs20\ql may give Dr. Charpentier the right to terminate our license rights. We will need to outsource and rely on third parties for many\plain\cf1\f51\fs20\ql aspects of the clinical development of the products covered under our license agreements. Delay or failure by these third parties\plain\cf1\f51\fs20\ql could adversely affect our ability to meet our diligence obligations and the continuation of our license agreements with\plain\cf1\f51\fs20\ql third-party licensors.\par\pard\plain\sb264\cf1\f51\fs20\qc 64\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Some Of Our In-licensed Patent Applications Are Subject To Priority Disputes And Inventorship Disputes. Our Owned And\plain\cf1\f51\fs20\i\ql In-Licensed Patents And Other Intellectual Property May Be Subject To Further Priority Disputes Or To Inventorship Disputes\plain\cf1\f51\fs20\i\ql And Similar Proceedings. If We Or Our Licensors Are Unsuccessful In Any Of These Proceedings, We May Be Required To\plain\cf1\f51\fs20\i\ql Obtain Licenses From Third Parties, Which May Not Be Available On Commercially Reasonable Terms Or At All, Or To Cease\plain\cf1\f51\fs20\i\ql The Development, Manufacture, And Commercialization Of One Or More Of The Product Candidates We May Develop, Which\plain\cf1\f51\fs20\i\ql Could Have A Material Adverse Impact On Our Business.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql In January 2016, at our request, the USPTO declared an interference between one of the pending U.S. patent applications\plain\cf1\f51\fs20\ql we licensed from Dr. Charpentier and twelve issued U.S. patents, and subsequently added one U.S. patent application, owned\plain\cf1\f51\fs20\ql jointly by the Broad Institute and Massachusetts Institute of Technology and, in some instances, the President and Fellows of\plain\cf1\f51\fs20\ql Harvard College, collectively referred to as the Broad. An interference is a proceeding conducted at the USPTO by the Patent\plain\cf1\f51\fs20\ql Trial and Appeal Board, or PTAB, to determine which party was the first to invent subject matter claimed by both of these\plain\cf1\f51\fs20\ql parties. There were two parties to this interference. Because our application was filed first, the USPTO designated\plain\cf1\f51\fs20\ql Dr.\~Charpentier, the Regents of the University of California, or California, and the University of Vienna, or Vienna, collectively\plain\cf1\f51\fs20\ql as \u8220?Senior Party\u8221? and designated Broad as \u8220?Junior Party.\u8221? Following motions by the parties and other\plain\cf1\f51\fs20\ql procedural matters, the PTAB concluded in February 2017 that the declared interference should be dismissed because the claim\plain\cf1\f51\fs20\ql sets of the two parties were not directed to the same patentable invention in accordance with the PTAB\u8217?s two-way test for\plain\cf1\f51\fs20\ql patent interferences. In particular, the Junior Party\u8217?s claims in the interference were all limited to uses in eukaryotic cells,\plain\cf1\f51\fs20\ql while the Senior Party\u8217?s claims in the interference were not limited to uses in eukaryotic cells but included uses in all\plain\cf1\f51\fs20\ql settings. In April 2017, the Senior Party appealed the PTAB decision to the Federal Circuit, seeking review and reversal of the\plain\cf1\f51\fs20\ql PTAB\u8217?s February 2017 decision, which terminated the interference without determining which inventors actually invented\plain\cf1\f51\fs20\ql the use of the CRISPR/Cas9 genome editing technology in eukaryotic cells. In parallel, either party can pursue existing or new\plain\cf1\f51\fs20\ql patent applications in the U.S. and elsewhere. For example, one of the Broad\u8217?s pending patent applications (U.S. Serial\plain\cf1\f51\fs20\ql No. 14/523,799)\~\~issued as U.S. Patent No. 9,840,713 on December 12, 2017. Going forward, either party as well as other parties\plain\cf1\f51\fs20\ql could seek a new interference related to the uses of the technology in eukaryotic cells or other aspects of the technology, and any\plain\cf1\f51\fs20\ql existing or new patents could be the subject of other challenges to their validity of enforceability. In the context of a second\plain\cf1\f51\fs20\ql interference or in other proceedings, a determination could be reached regarding that the Senior Party was not the first to invent,\plain\cf1\f51\fs20\ql or it could be concluded that the contested subject matter is not patentable to the Senior Party and is patentable to the Junior\plain\cf1\f51\fs20\ql Party, which in this case could preclude our U.S. patent applications from issuing as patents, in which case the proceedings\plain\cf1\f51\fs20\ql would result in our losing the right to protect core innovations and our freedom to practice our core gene editing technology. If\plain\cf1\f51\fs20\ql there is a second interference, either party can again appeal an adverse decision to the U.S. Court of Appeals for the Federal\plain\cf1\f51\fs20\ql Circuit. In any case, it may be years before there is a final determination on priority. Pursuant to the terms of the license\plain\cf1\f51\fs20\ql agreement with Dr. Charpentier, we are responsible for covering or reimbursing Dr. Charpentier\u8217?s patent prosecution\plain\cf1\f51\fs20\ql defense and related costs associated with our in-licensed technology.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Furthermore, we may be involved in other interference proceedings or other disputes in the future. For example,\plain\cf1\f51\fs20\ql Toolgen\~Inc., or Toolgen, filed Suggestions of Interference in the USPTO on April\~13, 2015, and December\~3, 2015, suggesting\plain\cf1\f51\fs20\ql that they believe some of the claims in pending U.S. applications owned by Toolgen (U.S. Serial\~No.\~14/685,568 and U.S. Serial\plain\cf1\f51\fs20\ql No.\~14/685,510, respectively) interfere with certain claims in five of the Broad patents currently involved in the interference with\plain\cf1\f51\fs20\ql Dr. Charpentier, California and Vienna. The USPTO may, in the future, declare an interference between our patent application\plain\cf1\f51\fs20\ql and one or more Toolgen patent applications. We are also aware of additional third parties that have pending patent applications\plain\cf1\f51\fs20\ql relating to CRISPR technologies, which similarly may or may not lead to further interference proceedings. For example,\plain\cf1\f51\fs20\ql Rockefeller University has filed an application (U.S. Serial No.\~15/217,489) claiming priority to an application filed by the Broad,\plain\cf1\f51\fs20\ql but which names Rockefeller\u8217?s employee Luciano Marraffini as co-inventor of CRISPR/Cas9 technology; Vilnius\plain\cf1\f51\fs20\ql University has filed applications in the United States and in other jurisdictions (published internationally as WO2013/141680 and\plain\cf1\f51\fs20\ql WO2013/142578 and granted as a patent in the United States as U.S. Patent No. 9,637,739), Harvard University has filed\plain\cf1\f51\fs20\ql applications in the United States and in other jurisdictions (published internationally as WO2014/099744 and granted as a patent\plain\cf1\f51\fs20\ql in the United States as U.S. Patent No. 9,023,649), and Sigma-Aldrich has filed applications in the United States and in other\plain\cf1\f51\fs20\ql jurisdictions (published internationally as WO2014/089290), each claiming aspects of CRISPR/Cas9 technology based on\plain\cf1\f51\fs20\ql applications claiming priority to provisional filings in 2012. Numerous other filings are based on provisional applications filed\plain\cf1\f51\fs20\ql after 2012.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Broad, Toolgen, Vilnius, Harvard, Sigma-Aldrich and other parties routinely file international counterparts of their U.S.\plain\cf1\f51\fs20\ql applications, some of which have been granted or could in future be granted in Europe and/or other non-U.S. jurisdictions. We\plain\cf1\f51\fs20\ql and third parties have initiated opposition proceedings against some of these grants, and we may in the future oppose other grants\plain\cf1\f51\fs20\ql to these or other applicants. For example, we and eight other entities have opposed European Patent 2771468 that was granted to\plain\cf1\f51\fs20\ql Broad, MIT and Harvard. In hearings which began on January 16, 2018, the patent granted to Broad, MIT and Harvard was\plain\cf1\f51\fs20\ql revoked, but the patentees are expected to appeal the decision against them. Oppositions are also now pending with respect to a\plain\cf1\f51\fs20\ql number of other patents granted to them in Europe. Similarly, our intellectual property may in the future become involved in\plain\cf1\f51\fs20\ql opposition proceedings in Europe or other jurisdictions. For example, the issued European patent we in-licensed from Dr.\plain\cf1\f51\fs20\ql Charpentier has been opposed by multiple third parties. The opposition to the European patent could lead to the revocation of the\plain\cf1\f51\fs20\ql patents in whole or in part, or could lead to the claims being narrowed in a way that could impair or preclude our ability to\plain\cf1\f51\fs20\ql enforce the patent against competitors in Europe.\par\pard\plain\sb264\cf1\f51\fs20\qc 65\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql If we or our licensors are unsuccessful in any interference proceedings or other priority or validity disputes (including any\plain\cf1\f51\fs20\ql patent oppositions) to which we or they are subject or become subject to, we may lose valuable intellectual property rights\plain\cf1\f51\fs20\ql through the loss or narrowing of one or more of our patent applications. If we or our licensors are unsuccessful in any\plain\cf1\f51\fs20\ql interference proceeding or other dispute, we may be required to seek to obtain and maintain licenses from third parties, including\plain\cf1\f51\fs20\ql parties involved in any such interference proceedings or other disputes. These third parties would be under no obligation to grant\plain\cf1\f51\fs20\ql to us any such license and such licenses may not be available on commercially reasonable terms or at all, or may be\plain\cf1\f51\fs20\ql non-exclusive. If we are unable to obtain and maintain such licenses, we and our partners may need to cease the practice of our\plain\cf1\f51\fs20\ql core gene editing, and the development, manufacture, and commercialization of one or more of the product candidates we may\plain\cf1\f51\fs20\ql develop. The loss of exclusivity or the narrowing of our patent claims could limit our ability to stop others from using or\plain\cf1\f51\fs20\ql commercializing similar or identical technology and products. Any of the foregoing could result in a material adverse effect on\plain\cf1\f51\fs20\ql our business, financial condition, results of operations, or prospects. If we are unsuccessful in our dispute with Broad, we and our\plain\cf1\f51\fs20\ql partners may be blocked from commercializing any products based on our core gene editing technology. Even if we are\plain\cf1\f51\fs20\ql successful in an interference proceeding or other similar disputes, it could result in substantial costs and be a distraction to\plain\cf1\f51\fs20\ql management and other employees.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql The Intellectual Property That Protects Our Core Gene Editing Technology Is Jointly Owned, And Our License Is From\plain\cf1\f51\fs20\i\ql Only One Of The Joint Owners, Materially Limiting Our Rights In The United States And In Other Jurisdictions.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql The family of patent applications we have in-licensed from Dr. Charpentier is the foundational patent protection for our\plain\cf1\f51\fs20\ql core gene editing technology. However, that family includes other named inventors who assigned their rights either to California\plain\cf1\f51\fs20\ql or to Vienna. As such, the intellectual property is currently co-owned by Dr.\~Charpentier, California, and Vienna. On December\plain\cf1\f51\fs20\ql 15, 2016, we entered into a Consent to Assignments, Licensing and Common Ownership and Invention Management Agreement,\plain\cf1\f51\fs20\ql or IMA, with California, Vienna and their licensees including Caribou Biosciences, Inc. and Caribou\u8217?s licensee Intellia\plain\cf1\f51\fs20\ql Therapeutics, Inc. Under the IMA, the co-owners provided reciprocal worldwide cross-consents to each of the other\plain\cf1\f51\fs20\ql co-owners\u8217? licensees and sublicensees, and agreed to a number of other commitments and obligations with respect to\plain\cf1\f51\fs20\ql supporting and managing the underlying CRISPR/Cas9 gene editing intellectual property, including a cost-sharing agreement. As\plain\cf1\f51\fs20\ql explained more fully below, that leaves us in a position of holding only non-exclusive or co-exclusive rights to the patent rights\plain\cf1\f51\fs20\ql that protect our core gene editing technology, and we must continue to satisfy our contractual obligations under the IMA in order\plain\cf1\f51\fs20\ql to maintain the effectiveness of the consents by California and Vienna to our license from Dr. Charpentier.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In the United States, each co-owner has the freedom to license and exploit the technology. As a result, we do not have\plain\cf1\f51\fs20\ql exclusive access to any intellectual property rights that Dr. Charpentier co-owns with another entity, such as California and\plain\cf1\f51\fs20\ql Vienna. Our license with Dr.\~Charpentier is therefore non-exclusive with respect to such co-owned rights. Furthermore, in the\plain\cf1\f51\fs20\ql United States each co-owner is required to be joined as a party to any claim or action we may wish to bring to enforce those\plain\cf1\f51\fs20\ql patent rights. Moreover, in the United States, non-exclusive licenses have no standing to bring a patent infringement action\plain\cf1\f51\fs20\ql before a court. Therefore, for the patents owned with California and Vienna we have no ability to pursue third party infringement\plain\cf1\f51\fs20\ql claims without cooperation of California and Vienna and potentially their licensees. Although we have entered into a Consent to\plain\cf1\f51\fs20\ql Assignments, Licensing and Common Ownership and Invention Management Agreement with Vienna and California and their\plain\cf1\f51\fs20\ql licensees, which provides for, among other things, notice of and coordination in the event of third-party infringement of the\plain\cf1\f51\fs20\ql CRISPR/Cas9 intellectual property, there can be no assurance that Vienna and California will cooperate with us in any future\plain\cf1\f51\fs20\ql infringement. If we are unable to enforce our core patent rights licensed from Dr.\~Charpentier, we may be unable to prevent third\plain\cf1\f51\fs20\ql parties from competing with us and may be unable to persuade companies to sublicense our technology, either of which could\plain\cf1\f51\fs20\ql have a material adverse effect on our business.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql If We Experience Disputes With The Third Parties That We In-license Intellectual Property Rights From, We Could Lose\plain\cf1\f51\fs20\i\ql License Rights That Are Important To Our Business.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We license our foundational intellectual property from a third party, and we expect to continue to in-license additional\plain\cf1\f51\fs20\ql third-party intellectual property rights as we expand our CRISPR/Cas9 gene-editing technology. Disputes may arise with the\plain\cf1\f51\fs20\ql third parties from whom we license our intellectual property rights from for a variety of reasons, including:
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\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql the priority of invention of patented technology.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\sb264\fi528\cf1\f51\fs20\ql In addition, the agreements under which we currently license intellectual property or technology from third parties, or\plain\cf1\f51\fs20\ql maintain consents under the IMA, are complex, and certain provisions in such agreements may be susceptible to multiple\plain\cf1\f51\fs20\ql interpretations, or may conflict in such a way that puts us in breach of one or more agreements, which would make us\plain\cf1\f51\fs20\ql susceptible to lengthy and expensive disputes with one or more of our licensing partners or the parties to the IMA. The resolution\plain\cf1\f51\fs20\ql of any contract interpretation disagreement that may arise could narrow what we believe to be the scope of our rights to the\plain\cf1\f51\fs20\ql relevant intellectual property or technology, or increase what we believe to be our financial or other obligations under the\plain\cf1\f51\fs20\ql relevant agreement, either of which could have a material adverse effect on our business, financial condition, results of\plain\cf1\f51\fs20\ql operations, and prospects. Moreover, if disputes over intellectual property that we have licensed prevent or impair our ability to\plain\cf1\f51\fs20\ql maintain our current licensing arrangements on commercially acceptable terms, we may be unable to successfully develop and\plain\cf1\f51\fs20\ql commercialize the affected product candidates, which could have a material adverse effect on our business, financial conditions,\plain\cf1\f51\fs20\ql results of operations, and prospects.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql We May Not Be Successful In Obtaining Necessary Rights To Any Product Candidates We May Develop Through\plain\cf1\f51\fs20\i\ql Acquisitions And In-licenses.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We currently have rights to intellectual property, through in-licenses from third parties, to identify and develop product\plain\cf1\f51\fs20\ql candidates. Many pharmaceutical companies, biotechnology companies, and academic institutions are competing with us in the\plain\cf1\f51\fs20\ql field of gene-editing technology and filing patent applications potentially relevant to our business. For example, we are aware of\plain\cf1\f51\fs20\ql several third-party patent applications that, if issued, may be construed to cover our CRISPR/Cas9 technology and product\plain\cf1\f51\fs20\ql candidates. In order to avoid infringing these third-party patents, we may find it necessary or prudent to obtain licenses from\plain\cf1\f51\fs20\ql such third party intellectual property holders. We may also require licenses from third parties for certain modified or improved\plain\cf1\f51\fs20\ql components of CRISPR/Cas9 technology, such as modified nucleic acids, as well as non-CRISPR/Cas9 technologies such as\plain\cf1\f51\fs20\ql delivery methods that we are evaluating for use with product candidates we may develop. In addition, with respect to any patents\plain\cf1\f51\fs20\ql we co-own with third parties, we may require licenses to such co-owners\u8217? interest to such patents. However, we may be\plain\cf1\f51\fs20\ql unable to secure such licenses or otherwise acquire or in-license any compositions, methods of use, processes, or other\plain\cf1\f51\fs20\ql intellectual property rights from third parties that we identify as necessary for product candidates we may develop and\plain\cf1\f51\fs20\ql CRISPR/Cas9 technology. The licensing or acquisition of third party intellectual property rights is a competitive area, and several\plain\cf1\f51\fs20\ql more established companies may pursue strategies to license or acquire third party intellectual property rights that we may\plain\cf1\f51\fs20\ql consider attractive or necessary. These established companies may have a competitive advantage over us due to their size, capital\plain\cf1\f51\fs20\ql resources and greater clinical development and commercialization capabilities. In addition, companies that perceive us to be a\plain\cf1\f51\fs20\ql competitor may be unwilling to assign or license rights to us. We also may be unable to license or acquire third party intellectual\plain\cf1\f51\fs20\ql property rights on terms that would allow us to make an appropriate return on our investment or at all. If we are unable to\plain\cf1\f51\fs20\ql successfully obtain rights to required third party intellectual property rights or maintain the existing intellectual property rights we\plain\cf1\f51\fs20\ql have, we may have to abandon development of the relevant program or product candidate, or discontinue the practice of our core\plain\cf1\f51\fs20\ql CRISPR/Cas9 gene-editing technology, which could have a material adverse effect on our business, financial condition, results of\plain\cf1\f51\fs20\ql operations, and prospects.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Issued Patents Covering Our Technology And Product Candidates Could Be Found Invalid Or Unenforceable If Challenged\plain\cf1\f51\fs20\i\ql In Court.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql If we or one of our licensors initiated legal proceedings against a third party to enforce a patent covering a product\plain\cf1\f51\fs20\ql candidate we may develop or our technology, including CRISPR/Cas9, the defendant could counterclaim that such patent is\plain\cf1\f51\fs20\ql invalid or unenforceable. In patent litigation in the United States, defendant counterclaims alleging invalidity or unenforceability\plain\cf1\f51\fs20\ql are commonplace. Grounds for a validity challenge could be an alleged failure to meet any of several statutory requirements,\plain\cf1\f51\fs20\ql including lack of novelty, obviousness, or non-enablement.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Grounds for an unenforceability assertion could be an allegation that someone connected with prosecution of the patent\plain\cf1\f51\fs20\ql withheld relevant information from the USPTO, or made a misleading statement, during prosecution. Third parties have raised\plain\cf1\f51\fs20\ql challenges to the validity of certain of our in-licensed patent applications, such as our in-licensed CRISPR/Cas9 patent\plain\cf1\f51\fs20\ql applications in the context of third party observations and oppositions filed in Europe and Australia, and may in the future raise\plain\cf1\f51\fs20\ql similar claims before administrative bodies in the United States or in other jurisdictions, even outside the context of litigation.\plain\cf1\f51\fs20\ql Mechanisms for challenging the validity of patents in patent offices include re-examination, post-grant review,\plain\cf1\f51\fs20\i\ql inter partes\plain\cf1\f51\fs20\ql review, interference proceedings, derivation proceedings, and equivalent proceedings in non-U.S. jurisdictions (e.g.,\~opposition\plain\cf1\f51\fs20\ql proceedings). Such proceedings could result in the loss of our patent applications or patents, or their narrowing in such a way\plain\cf1\f51\fs20\ql that they no longer cover our technology or platform, or any product candidates that we may develop. The outcome following\plain\cf1\f51\fs20\ql legal assertions of invalidity and unenforceability is unpredictable. With respect to the validity question, for example, we cannot\plain\cf1\f51\fs20\ql be certain that there is no invalidating prior art. If a third party were to prevail on a legal assertion of invalidity or\plain\cf1\f51\fs20\ql unenforceability, we would lose at least part, and perhaps all, of the patent protection on our technology or platform, or any\plain\cf1\f51\fs20\ql product candidates that we may develop. Such a loss of patent protection would have a material adverse impact on our business,\plain\cf1\f51\fs20\ql financial condition, results of operations, and prospects.\par\pard\plain\sb264\cf1\f51\fs20\qc 67\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql The Intellectual Property Landscape Around Gene-Editing Technology, Including CRISPR/Cas9, Is Highly Dynamic, And\plain\cf1\f51\fs20\i\ql Third Parties May Initiate And Prevail In Legal Proceedings Alleging That The Patents That We In-License Or Own Are Invalid\plain\cf1\f51\fs20\i\ql Or That We Are Infringing, Misappropriating, Or Otherwise Violating Their Intellectual Property Rights, The Outcome Of Which\plain\cf1\f51\fs20\i\ql Would Be Uncertain And Could Have A Material Adverse Effect On The Success Of Our Business.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql The field of gene editing, especially in the area of CRISPR/Cas9 technology, is still in its infancy, and no such products\plain\cf1\f51\fs20\ql have reached the market. Due to the intense research and development that is taking place by several companies, including us\plain\cf1\f51\fs20\ql and our competitors, in this field, the intellectual property landscape is in flux, and it may remain uncertain for the coming years.\plain\cf1\f51\fs20\ql There may be significant intellectual property related litigation and proceedings, in addition to the ongoing interference\plain\cf1\f51\fs20\ql proceedings, relating to our owned and in-licensed, and other third party, intellectual property and proprietary rights in the future.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Our commercial success depends upon our ability and the ability of our collaborators to develop, manufacture, market, and\plain\cf1\f51\fs20\ql sell any product candidates that we may develop and use our proprietary technologies without infringing, misappropriating, or\plain\cf1\f51\fs20\ql otherwise violating the intellectual property and proprietary rights of third parties. The biotechnology and pharmaceutical\plain\cf1\f51\fs20\ql industries are characterized by extensive litigation regarding patents and other intellectual property rights. We are subject to and\plain\cf1\f51\fs20\ql may in the future become party to, or threatened with, adversarial proceedings or litigation regarding intellectual property rights\plain\cf1\f51\fs20\ql with respect to our technology and any product candidates we may develop, including re-examination interference proceedings,\plain\cf1\f51\fs20\ql post-grant review,\plain\cf1\f51\fs20\i\ql inter partes\plain\cf1\f51\fs20\ql review, and derivation proceedings before the USPTO and similar proceedings in other\plain\cf1\f51\fs20\ql jurisdictions such as oppositions before the European Patent Office. Third parties, including parties involved in ongoing\plain\cf1\f51\fs20\ql interference proceedings, may assert infringement claims against us based on existing patents or patents that may be granted in\plain\cf1\f51\fs20\ql the future, regardless of their merit. We are aware of certain third-party patents and patent applications including, for example,\plain\cf1\f51\fs20\ql the Broad, Vilnius, Harvard and Sigma-Aldrich patents described above, that may be asserted to encompass our CRISPR/Cas9\plain\cf1\f51\fs20\ql technology. If we are unable to prove that these patents are invalid and we are not able to obtain or maintain a license on\plain\cf1\f51\fs20\ql commercially reasonable terms, such third parties could potentially assert infringement claims against us, which could have a\plain\cf1\f51\fs20\ql material adverse effect on the conduct of our business. If we are found to infringe such third-party patents, we and our partners\plain\cf1\f51\fs20\ql may be required to pay damages, cease commercialization of the infringing technology, including our core CRISPR/Cas9\plain\cf1\f51\fs20\ql gene-editing technology, or obtain a license from such third parties, which may not be available on commercially reasonable\plain\cf1\f51\fs20\ql terms or at all. Additionally, we have not performed any freedom-to-operate analysis on specific product candidates at this stage\plain\cf1\f51\fs20\ql to identify potential infringement risks. A proper analysis of that type will not be feasible until specific product candidates are\plain\cf1\f51\fs20\ql designed.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Even if we believe third-party intellectual property claims are without merit, there is no assurance that a court would find\plain\cf1\f51\fs20\ql in our favor on questions of infringement, validity, enforceability, ownership, or priority. A court of competent jurisdiction could\plain\cf1\f51\fs20\ql hold that these third-party patents are valid, enforceable, and infringed, which could materially and adversely affect our ability to\plain\cf1\f51\fs20\ql commercialize any product candidates we may develop and any other product candidates or technologies covered by the asserted\plain\cf1\f51\fs20\ql third-party patents. In order to successfully challenge the validity of any such U.S. patent in federal court, we would need to\plain\cf1\f51\fs20\ql overcome a presumption of validity. As this burden is a high one requiring us to present clear and convincing evidence as to the\plain\cf1\f51\fs20\ql invalidity of any such U.S. patent claim, there is no assurance that a court of competent jurisdiction would invalidate the claims\plain\cf1\f51\fs20\ql of any such U.S. patent. If we are found to infringe a third party\u8217?s intellectual property rights, and we are unsuccessful in\plain\cf1\f51\fs20\ql demonstrating that such patents are invalid or unenforceable, we could be required to obtain a license from such third party to\plain\cf1\f51\fs20\ql continue developing, manufacturing, and marketing any product candidates we may develop and our technology. However, we\plain\cf1\f51\fs20\ql may not be able to obtain any required license on commercially reasonable terms or at all. Even if we were able to obtain a\plain\cf1\f51\fs20\ql license, it could be non-exclusive, thereby giving our competitors and other third parties access to the same technologies licensed\plain\cf1\f51\fs20\ql to us, and it could require us to make substantial licensing and royalty payments. We also could be forced, including by court\plain\cf1\f51\fs20\ql order, to cease developing, manufacturing, and commercializing the infringing technology or product candidates. In addition, we\plain\cf1\f51\fs20\ql could be found liable for significant monetary damages, including treble damages and attorneys\u8217? fees, if we are found to\plain\cf1\f51\fs20\ql have willfully infringed a patent or other intellectual property right. Claims that we have misappropriated the confidential\plain\cf1\f51\fs20\ql information or trade secrets of third parties could have a similar material adverse effect on our business, financial condition,\plain\cf1\f51\fs20\ql results of operations, and prospects.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Intellectual Property Litigation Could Cause Us To Spend Substantial Resources And Distract Our Personnel From Their\plain\cf1\f51\fs20\i\ql Normal Responsibilities.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Litigation or other legal proceedings relating to intellectual property claims, with or without merit, is unpredictable and\plain\cf1\f51\fs20\ql generally expensive and time-consuming and is likely to divert significant resources from our core business, including distracting\plain\cf1\f51\fs20\ql our technical and management personnel from their normal responsibilities and generally harm our business. Furthermore,\plain\cf1\f51\fs20\ql because of the substantial amount of discovery required in connection with intellectual property litigation in certain countries,\plain\cf1\f51\fs20\ql including the United States, there is a risk that some of our confidential information could be compromised by disclosure during\plain\cf1\f51\fs20\ql this type of litigation. In addition, there could be public announcements of the results of hearings, motions or other interim\plain\cf1\f51\fs20\ql proceedings or developments and if securities analysts or investors perceive these results to be negative, it could have a\plain\cf1\f51\fs20\ql substantial adverse effect on the price of our common shares. Such litigation or proceedings could substantially increase our\plain\cf1\f51\fs20\ql operating losses and reduce the resources available for development activities or any future sales, marketing or distribution\plain\cf1\f51\fs20\ql activities.\par\pard\plain\sb264\cf1\f51\fs20\qc 68\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We may not have sufficient financial or other resources to adequately conduct such litigation or proceedings. Some of our\plain\cf1\f51\fs20\ql competitors may be able to sustain the costs of such litigation or proceedings more effectively than we can because of their\plain\cf1\f51\fs20\ql greater financial resources. Accordingly, despite our efforts, we may not be able to prevent third parties from infringing or\plain\cf1\f51\fs20\ql misappropriating or successfully challenging our intellectual property rights. Uncertainties resulting from the initiation and\plain\cf1\f51\fs20\ql continuation of patent litigation or other proceedings could have a material adverse effect on our ability to compete in the\plain\cf1\f51\fs20\ql marketplace.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Obtaining And Maintaining Our Patent Protection Depends On Compliance With Various Procedural, Document\plain\cf1\f51\fs20\i\ql Submission, Fee Payment, And Other Requirements Imposed By Government Patent Agencies And Our Patent Protection Could\plain\cf1\f51\fs20\i\ql Be Reduced Or Eliminated For Non-compliance With These Requirements.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Periodic maintenance fees, renewal fees, annuity fees and various other government fees on patents and applications will be\plain\cf1\f51\fs20\ql due to be paid to the USPTO and various government patent agencies outside of the United States over the lifetime of our owned\plain\cf1\f51\fs20\ql or licensed patents and applications. In certain circumstances, we rely on our licensing partners to pay these fees due to U.S. and\plain\cf1\f51\fs20\ql non-U.S. patent agencies. The USPTO and various non-U.S. government agencies require compliance with several procedural,\plain\cf1\f51\fs20\ql documentary, fee payment, and other similar provisions during the patent application process. In addition, periodic maintenance\plain\cf1\f51\fs20\ql fees on issued patents\~often must be paid to the USPTO and other patent agencies over the lifetime of the patent. We are also\plain\cf1\f51\fs20\ql dependent on our licensors to take the necessary action to comply with these requirements with respect to our licensed\plain\cf1\f51\fs20\ql intellectual property. In some cases, an inadvertent lapse can be cured by payment of a late fee or by other means in accordance\plain\cf1\f51\fs20\ql with the applicable rules. There are situations, however, in which non-compliance can result in abandonment or lapse of the\plain\cf1\f51\fs20\ql patent or patent application, resulting in a partial or complete loss of patent rights in the relevant jurisdiction. Non-compliance\plain\cf1\f51\fs20\ql events that could result in abandonment or lapse of a patent or patent application include, but are not limited to, failure to\plain\cf1\f51\fs20\ql respond to official actions within prescribed time limits, non-payment of fees and failure to properly legalize and submit formal\plain\cf1\f51\fs20\ql documents. If we or our licensors fail to maintain the patents and patent applications covering our product candidates, we may\plain\cf1\f51\fs20\ql not be able to stop a competitor from marketing drugs that are the same as or similar to our product candidates, which would\plain\cf1\f51\fs20\ql have a material adverse effect on our business.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Some Intellectual Property Which We Have In-licensed May Have Been Discovered Through Government Funded\plain\cf1\f51\fs20\i\ql Programs And Thus May Be Subject To Federal Regulations Such As \u8220?march-in\u8221? Rights, Certain Reporting\plain\cf1\f51\fs20\i\ql Requirements And A Preference For U.S.-based Manufacturers. Compliance With Such Regulations May Limit Our Exclusive\plain\cf1\f51\fs20\i\ql Rights, And Limit Our Ability To Contract With Non-U.S. Manufacturers.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql The intellectual property rights to which we have in-licensed under Dr. Charpentier\u8217?s joint interest are co-owned by\plain\cf1\f51\fs20\ql California, which has indicated that the invention was made under Grant No. GM081879 awarded by the National Institute of\plain\cf1\f51\fs20\ql Health. These rights are therefore subject to certain federal regulations. The U.S. government has certain rights pursuant to the\plain\cf1\f51\fs20\ql Bayh-Dole Act of 1980, or Bayh-Dole Act, to patents covering government rights in certain inventions developed under a\plain\cf1\f51\fs20\ql government-funded program. These rights include a non-exclusive, non-transferable, irrevocable worldwide license to use\plain\cf1\f51\fs20\ql inventions for any governmental purpose. In addition, the U.S. government has the right to require us to grant exclusive, partially\plain\cf1\f51\fs20\ql exclusive, or non-exclusive licenses to any of these inventions to a third party if it determines that: (i)\~adequate steps have not\plain\cf1\f51\fs20\ql been taken to commercialize the invention; (ii)\~government action is necessary to meet public health or safety needs; or\plain\cf1\f51\fs20\ql (iii)\~government action is necessary to meet requirements for public use under federal regulations, also referred to as\plain\cf1\f51\fs20\ql \u8220?march-in rights.\u8221? The U.S. government also has the right to take title to these inventions if we, or the applicable\plain\cf1\f51\fs20\ql contractor, fail to disclose the invention to the government and fail to file an application to register the intellectual property\plain\cf1\f51\fs20\ql within specified time limits. Intellectual property generated under a government funded program is also subject to certain\plain\cf1\f51\fs20\ql reporting requirements, compliance with which may require us or the applicable contractor to expend substantial resources. In\plain\cf1\f51\fs20\ql addition, the U.S. government requires that any products embodying the subject invention or produced through the use of the\plain\cf1\f51\fs20\ql subject invention be manufactured substantially in the United States. The manufacturing preference requirement can be waived if\plain\cf1\f51\fs20\ql the owner of the intellectual property can show that reasonable but unsuccessful efforts have been made to grant licenses on\plain\cf1\f51\fs20\ql similar terms to potential licensees that would be likely to manufacture substantially in the United States or that under the\plain\cf1\f51\fs20\ql circumstances domestic manufacture is not commercially feasible. This preference for U.S. manufacturers may limit our ability to\plain\cf1\f51\fs20\ql contract with non-U.S. product manufacturers for products covered by such intellectual property. To the extent any of our current\plain\cf1\f51\fs20\ql or future patents covering inventions is generated through the use of U.S. government funding, the provisions of the Bayh-Dole\plain\cf1\f51\fs20\ql Act may similarly apply.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql We May Not Be Able To Protect Our Intellectual Property And Proprietary Rights Throughout The World.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Filing, prosecuting and defending patents on our product candidates in all countries throughout the world would be\plain\cf1\f51\fs20\ql prohibitively expensive. The requirements for patentability may differ in certain countries, particularly in developing countries.\plain\cf1\f51\fs20\ql Moreover, our ability to protect and enforce our intellectual property rights may be adversely affected by unforeseen changes in\plain\cf1\f51\fs20\ql intellectual property laws various jurisdictions worldwide. Additionally, the patent laws of some countries do not afford\plain\cf1\f51\fs20\ql intellectual property protection to the same extent as the laws of the United States. For example, unlike patent law in the United\plain\cf1\f51\fs20\ql States, the patent law in Europe and many other jurisdictions precludes the patentability of methods of treatment of the human\plain\cf1\f51\fs20\ql body and imposes substantial restrictions on the scope of claims it will grant if broader than specifically disclosed embodiments.\par\pard\plain\sb264\cf1\f51\fs20\qc 69\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Many companies have encountered significant problems in protecting and defending intellectual property rights in various\plain\cf1\f51\fs20\ql jurisdictions globally. Consequently, we may not be able to prevent third parties from practicing our inventions in all countries\plain\cf1\f51\fs20\ql outside the United States, or from selling or importing products made using our inventions in and into the United States or other\plain\cf1\f51\fs20\ql jurisdictions. Competitors may use our technologies in jurisdictions where we have not pursued and obtained patent protection to\plain\cf1\f51\fs20\ql develop their own products and, further, may export otherwise infringing products to territories where we have patent protection\plain\cf1\f51\fs20\ql but enforcement is not as strong as that in the United States. These products may compete with our product candidates, and our\plain\cf1\f51\fs20\ql patents or other intellectual property rights may not be effective or sufficient to prevent them from competing. The legal systems\plain\cf1\f51\fs20\ql of certain countries, particularly certain developing countries, do not favor the enforcement of patents, trade secrets, and other\plain\cf1\f51\fs20\ql intellectual property protection, particularly those relating to biotechnology products, which could make it difficult for us to stop\plain\cf1\f51\fs20\ql the infringement of our patents or marketing of competing products in violation of our intellectual property and proprietary rights\plain\cf1\f51\fs20\ql generally. Proceedings to enforce our intellectual property and proprietary rights in various jurisdictions globally could result in\plain\cf1\f51\fs20\ql substantial costs and divert our efforts and attention from other aspects of our business, could put our patents at risk of being\plain\cf1\f51\fs20\ql invalidated or interpreted narrowly, could put our patent applications at risk of not issuing, and could provoke third parties to\plain\cf1\f51\fs20\ql assert claims against us. We may not prevail in any lawsuits that we initiate, and the damages or other remedies awarded, if any,\plain\cf1\f51\fs20\ql may not be commercially meaningful. Accordingly, our efforts to enforce our intellectual property and proprietary rights around\plain\cf1\f51\fs20\ql the world may be inadequate to obtain a significant commercial advantage from the intellectual property that we develop or\plain\cf1\f51\fs20\ql license.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Many countries have compulsory licensing laws under which a patent owner may be compelled to grant licenses to third\plain\cf1\f51\fs20\ql parties. In addition, many countries limit the enforceability of patents against third parties, including government agencies or\plain\cf1\f51\fs20\ql government contractors. In these countries, the patent owner may have limited remedies, which could materially diminish the\plain\cf1\f51\fs20\ql value of such patent. If we or any of our licensors is forced to grant a license to third parties with respect to any patents relevant\plain\cf1\f51\fs20\ql to our business, our competitive position may be impaired, and our business, financial condition, results of operations, and\plain\cf1\f51\fs20\ql prospects may be adversely affected. Patent protection must ultimately be sought on a country-by-country basis, which is an\plain\cf1\f51\fs20\ql expensive and time-consuming process with uncertain outcomes. Accordingly, we may choose not to seek patent protection in\plain\cf1\f51\fs20\ql certain countries, and we will not have the benefit of patent protection in such countries.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Changes To The Patent Law In The United States And Other Jurisdictions Could Diminish The Value Of Patents In\plain\cf1\f51\fs20\i\ql General, Thereby Impairing Our Ability To Protect Our Product Candidates.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql As is the case with other biopharmaceutical companies, our success is heavily dependent on intellectual property,\plain\cf1\f51\fs20\ql particularly patents. Obtaining and enforcing patents in the biopharmaceutical industry involves both technological and legal\plain\cf1\f51\fs20\ql complexity and is therefore costly, time consuming and inherently uncertain. Recent patent reform legislation in the United States\plain\cf1\f51\fs20\ql and other countries, including the Leahy-Smith America Invents Act, or Leahy-Smith Act, signed into law on September\~16,\plain\cf1\f51\fs20\ql 2011, could increase those uncertainties and costs. The Leahy-Smith Act includes a number of significant changes to U.S. patent\plain\cf1\f51\fs20\ql law. These include provisions that affect the way patent applications are prosecuted, redefine prior art and provide more efficient\plain\cf1\f51\fs20\ql and cost-effective avenues for competitors to challenge the validity of patents. In addition, the Leahy-Smith Act has transformed\plain\cf1\f51\fs20\ql the U.S. patent system into a \u8220?first to file\u8221? system. The first-to-file provisions, however, only became effective on\plain\cf1\f51\fs20\ql March\~16, 2013. Accordingly, it is not yet clear what, if any, impact the Leahy-Smith Act will have on the operation of our\plain\cf1\f51\fs20\ql business. However, the Leahy-Smith Act and its implementation could make it more difficult to obtain patent protection for our\plain\cf1\f51\fs20\ql inventions and increase the uncertainties and costs surrounding the prosecution of our patent applications and the enforcement or\plain\cf1\f51\fs20\ql defense of our issued patents, all of which could harm our business, results of operations and financial condition.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql The U.S. Supreme Court has ruled on several patent cases in recent years, either narrowing the scope of patent protection\plain\cf1\f51\fs20\ql available in certain circumstances or weakening the rights of patent owners in certain situations. For example, in\plain\cf1\f51\fs20\i\ql Association for\plain\cf1\f51\fs20\i\ql Molecular Pathology v. Myriad Genetics, Inc\plain\cf1\f51\fs20\ql ., the Supreme Court ruled that a \u8220?naturally occurring DNA segment is a\plain\cf1\f51\fs20\ql product of nature and not patent eligible merely because it has been isolated,\u8221? and invalidated Myriad Genetics\u8217?\plain\cf1\f51\fs20\ql claims on the isolated BRCA1 and BRCA2 genes. Certain claims of our patents relate to CRISPR/Cas9 gene-editing technology\plain\cf1\f51\fs20\ql as well as guide components that are directed to naturally occurring DNA sequences. To the extent that such claims are deemed\plain\cf1\f51\fs20\ql to be directed to natural products, or to lack an inventive concept above and beyond an isolated natural product, a court may\plain\cf1\f51\fs20\ql decide the claims are invalid under\plain\cf1\f51\fs20\i\ql Myriad\plain\cf1\f51\fs20\ql . Additionally, there have been recent proposals for additional changes to the patent\plain\cf1\f51\fs20\ql laws of the United States and other countries that, if adopted, could impact our ability to obtain patent protection for our\plain\cf1\f51\fs20\ql proprietary technology or our ability to enforce our proprietary technology. Depending on future actions by the U.S. Congress,\plain\cf1\f51\fs20\ql the U.S. courts, the USPTO and the relevant law-making bodies in other countries, the laws and regulations governing patents\plain\cf1\f51\fs20\ql could change in unpredictable ways that would weaken our ability to obtain new patents or to enforce our existing patents and\plain\cf1\f51\fs20\ql patents that we might obtain in the future. Europe\u8217?s planned Unified Patent Court may particularly present uncertainties\plain\cf1\f51\fs20\ql for our ability to protect and enforce our patent rights against competitors in Europe. While that new court is being implemented\plain\cf1\f51\fs20\ql to provide more certainty and efficiency to patent enforcement throughout Europe, it will also provide our competitors with a\plain\cf1\f51\fs20\ql new forum to use to centrally revoke our European patents. It will be several years before we will understand the scope of patent\plain\cf1\f51\fs20\ql rights that will be recognized and the strength of patent remedies that will be provided by that court. We will have the right to\plain\cf1\f51\fs20\ql opt our patents out of that system over the first seven years of the court, but doing so may preclude us from realizing the\plain\cf1\f51\fs20\ql benefits of the new unified court.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb264\cf1\f51\fs20\qc 70\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb176\fi528\cf1\f51\fs20\i\ql If We Are Unable To Protect The Confidentiality Of Our Trade Secrets, Our Business And Competitive Position Would Be\plain\cf1\f51\fs20\i\ql Harmed.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql In addition to seeking patents for some of our technology and product candidates, we also rely on trade secrets and\plain\cf1\f51\fs20\ql confidentiality agreements to protect our unpatented know-how, technology, and other proprietary information and to maintain\plain\cf1\f51\fs20\ql our competitive position. Trade secrets and know-how can be difficult to protect. In particular, we anticipate that with respect to\plain\cf1\f51\fs20\ql our technology platform, these trade secrets and know-how will over time be disseminated within the industry through\plain\cf1\f51\fs20\ql independent development, the publication of journal articles describing the methodology, and the movement of personnel from\plain\cf1\f51\fs20\ql academic to industry scientific positions.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql We seek to protect these trade secrets and other proprietary technology, in part, by entering into non-disclosure and\plain\cf1\f51\fs20\ql confidentiality agreements with parties who have access to them, such as our employees, corporate collaborators, outside\plain\cf1\f51\fs20\ql scientific collaborators, CROs, contract manufacturers, consultants, advisors, and other third parties. We also enter into\plain\cf1\f51\fs20\ql confidentiality and invention or patent assignment agreements with our employees and consultants. We cannot guarantee that we\plain\cf1\f51\fs20\ql have entered into such agreements with each party that may have or have had access to our trade secrets or proprietary\plain\cf1\f51\fs20\ql technology and processes. Despite these efforts, any of these parties may breach the agreements and disclose our proprietary\plain\cf1\f51\fs20\ql information, including our trade secrets, and we may not be able to obtain adequate remedies for such breaches. Enforcing a\plain\cf1\f51\fs20\ql claim that a party illegally disclosed or misappropriated a trade secret is difficult, expensive, and time-consuming, and the\plain\cf1\f51\fs20\ql outcome is unpredictable. In addition, some courts inside and outside the United States are less willing or unwilling to protect\plain\cf1\f51\fs20\ql trade secrets. If any of our trade secrets were to be lawfully obtained or independently developed by a competitor or other third\plain\cf1\f51\fs20\ql party, we would have no right to prevent them, or those to whom they communicate it, from using that technology or information\plain\cf1\f51\fs20\ql to compete with us. If any of our trade secrets were to be disclosed to or independently developed by a competitor or other third\plain\cf1\f51\fs20\ql party, our competitive position would be materially and adversely harmed.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql If We Do Not Obtain Patent Term Extension And Data Exclusivity For Any Product Candidates We May Develop, Our\plain\cf1\f51\fs20\i\ql Business May Be Materially Harmed.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Depending upon the timing, duration and specifics of any FDA marketing approval of any product candidates we may\plain\cf1\f51\fs20\ql develop, one or more of our U.S. patents may be eligible for limited patent term extension under the Drug Price Competition and\plain\cf1\f51\fs20\ql Patent Term Restoration Action of 1984, or Hatch-Waxman Amendments. The Hatch-Waxman Amendments permit a patent\plain\cf1\f51\fs20\ql extension term of up to five years as compensation for patent term lost during the FDA regulatory review process. A patent term\plain\cf1\f51\fs20\ql extension cannot extend the remaining term of a patent beyond a total of 14\~years from the date of product approval, only one\plain\cf1\f51\fs20\ql patent may be extended and only those claims covering the approved drug, a method for using it, or a method for manufacturing\plain\cf1\f51\fs20\ql it may be extended. However, we may not be granted an extension because of, for example, failing to exercise due diligence\plain\cf1\f51\fs20\ql during the testing phase or regulatory review process, failing to apply within applicable deadlines, failing to apply prior to\plain\cf1\f51\fs20\ql expiration of relevant patents, or otherwise failing to satisfy applicable requirements. Moreover, the applicable time period or the\plain\cf1\f51\fs20\ql scope of patent protection afforded could be less than we request. If we are unable to obtain patent term extension or if the term\plain\cf1\f51\fs20\ql of any such extension is less than we request, we will be unable to rely on our patent position to forestall the marketing of\plain\cf1\f51\fs20\ql competing products following our patent expiration, and our business, financial condition, results of operations, and prospects\plain\cf1\f51\fs20\ql could be materially harmed.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Intellectual Property Rights Do Not Necessarily Address All Potential Threats.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql The degree of future protection afforded by our intellectual property rights is uncertain because intellectual property rights\plain\cf1\f51\fs20\ql have limitations and may not adequately protect our business or permit us to maintain our competitive advantage. For example:
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{\trowd\cellx432\cellx1116\cellx10800\trrh878
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql others may be able to make gene therapy products that are similar to any product candidates we may develop or\plain\intbl\cf1\f51\fs20\ql utilize similar gene therapy technology but that are not covered by the claims of the patents that we license or may\plain\intbl\cf1\f51\fs20\ql own in the future;\cell{
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\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql we, or our license partners or current or future collaborators, might not have been the first to make the inventions\plain\intbl\cf1\f51\fs20\ql covered by the issued patent or pending patent application that we license or may own in the future;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh495
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql we, or our license partners or current or future collaborators, might not have been the first to file patent applications\plain\intbl\cf1\f51\fs20\ql covering certain of our or their inventions;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh495
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql others may independently develop similar or alternative technologies or duplicate any of our technologies without\plain\intbl\cf1\f51\fs20\ql infringing our owned or licensed intellectual property rights;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh495
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql it is possible that our pending licensed patent applications or those that we may own in the future will not lead to\plain\intbl\cf1\f51\fs20\ql issued patents;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh495\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh0
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql issued patents that we hold rights to may be held invalid or unenforceable, including as a result of legal challenges\plain\intbl\cf1\f51\fs20\ql by our competitors;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh0\row}}}\pard\plain\sb264\cf1\f51\fs20\qc 71\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
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{\trowd\cellx432\cellx1116\cellx10800\trrh742
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql our competitors might conduct research and development activities in countries where we do not have patent rights\plain\intbl\cf1\f51\fs20\ql and then use the information learned from such activities to develop competitive products for sale in our major\plain\intbl\cf1\f51\fs20\ql commercial markets;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh742\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql we may not develop additional proprietary technologies that are patentable;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql the patents of others may harm our business; and\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh495
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql we may choose not to file\~a patent in order to maintain certain trade secrets or know-how, and a third party may\plain\intbl\cf1\f51\fs20\ql subsequently file\~a patent covering such intellectual property.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh495\row}}}{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\pard\plain\sb264\fi528\cf1\f51\fs20\ql Should any of these events occur, they could have a material adverse effect on our business, financial condition, results of\plain\cf1\f51\fs20\ql operations, and prospects.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql We May Be Subject To Claims That Our Employees, Consultants, Or Advisors Have Wrongfully Used Or Disclosed Alleged\plain\cf1\f51\fs20\i\ql Trade Secrets Of Their Current Or Former Employers Or Claims Asserting Ownership Of What We Regard As Our Own\plain\cf1\f51\fs20\i\ql Intellectual Property.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Many of our employees, consultants, and advisors are currently or were previously employed at universities or other\plain\cf1\f51\fs20\ql biotechnology or pharmaceutical companies. Although we try to ensure that our employees, consultants, and advisors do not use\plain\cf1\f51\fs20\ql the proprietary information or know-how of others in their work for us, we may be subject to claims that we or these individuals\plain\cf1\f51\fs20\ql have used or disclosed intellectual property, including trade secrets or other proprietary information, of any such\plain\cf1\f51\fs20\ql individual\u8217?s current or former employer. Litigation may be necessary to defend against these claims. If we fail in\plain\cf1\f51\fs20\ql defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights or\plain\cf1\f51\fs20\ql personnel. Even if we are successful in defending against such claims, litigation could result in substantial costs and be a\plain\cf1\f51\fs20\ql distraction to management.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In addition, while it is our policy to require our employees and contractors who may be involved in the conception or\plain\cf1\f51\fs20\ql development of intellectual property to execute agreements assigning such intellectual property to us, we may be unsuccessful in\plain\cf1\f51\fs20\ql executing such an agreement with each party who, in fact, conceives or develops intellectual property that we regard as our own.\plain\cf1\f51\fs20\ql The assignment of intellectual property rights may not be self-executing, or the assignment agreements may be breached, and we\plain\cf1\f51\fs20\ql may be forced to bring claims against third parties, or defend claims that they may bring against us, to determine the ownership\plain\cf1\f51\fs20\ql of what we regard as our intellectual property. Such claims could have a material adverse effect on our business, financial\plain\cf1\f51\fs20\ql condition, results of operations, and prospects.\par\pard\plain\sb396\cf1\f51\fs20\b\ql Risks Related to The Ownership of Our Common Shares\par\pard\plain\sb132\fi528\cf1\f51\fs20\i\ql We Will Incur Increased Costs As A Result Of Operating As A Public Company And Our Management Will Be Required To\plain\cf1\f51\fs20\i\ql Devote Substantial Time To New Compliance Initiatives And Corporate Governance Practices.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql As a public company, and particularly after we are no longer an \u8220?emerging growth company,\u8221? we will incur\plain\cf1\f51\fs20\ql significant legal, accounting and other expenses that we did not incur as a private company. SOX, the Dodd-Frank Wall Street\plain\cf1\f51\fs20\ql Reform and Consumer Protection Act, the listing requirements of The NASDAQ Global Market, and other applicable securities\plain\cf1\f51\fs20\ql rules and regulations impose various requirements on public companies, including establishment and maintenance of effective\plain\cf1\f51\fs20\ql disclosure and financial controls and corporate governance practices. Our management and other personnel will need to devote a\plain\cf1\f51\fs20\ql substantial amount of time towards maintaining compliance with these requirements. Moreover, these requirements will increase\plain\cf1\f51\fs20\ql our legal and financial compliance costs and will make some activities more time-consuming and costly. For example, the rules\plain\cf1\f51\fs20\ql and regulations may make it more difficult and more expensive for us to obtain director and officer liability insurance, which\plain\cf1\f51\fs20\ql could make it more difficult for us to attract and retain qualified members of our board of directors. We are currently evaluating\plain\cf1\f51\fs20\ql these rules and regulations and cannot predict or estimate the amount of additional costs we may incur or the timing of such\plain\cf1\f51\fs20\ql costs. These rules and regulations are often subject to varying interpretations, in many cases due to their lack of specificity, and,\plain\cf1\f51\fs20\ql as a result, their application in practice may evolve over time as new guidance is provided by regulatory and governing bodies.\plain\cf1\f51\fs20\ql This could result in continuing uncertainty regarding compliance matters and higher costs necessitated by ongoing revisions to\plain\cf1\f51\fs20\ql disclosure and governance practices.\par\pard\plain\sb264\cf1\f51\fs20\qc 72\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Pursuant to SOX Section\~404, we are required to furnish a report by our management on our internal control over financial\plain\cf1\f51\fs20\ql reporting, including an attestation report on internal control over financial reporting issued by our independent registered public\plain\cf1\f51\fs20\ql accounting firm. However, while we remain an emerging growth company, we will not be required to include an attestation\plain\cf1\f51\fs20\ql report on internal control over financial reporting issued by our independent registered public accounting firm. To achieve\plain\cf1\f51\fs20\ql compliance with SOX Section\~404 within the prescribed period, we are engaged in a process to document and evaluate our\plain\cf1\f51\fs20\ql internal control over financial reporting, which is both costly and challenging. In this regard, we will need to continue to dedicate\plain\cf1\f51\fs20\ql internal resources, potentially engage outside consultants, adopt a detailed work plan to assess and document the adequacy of\plain\cf1\f51\fs20\ql internal control over financial reporting, continue steps to improve control processes as appropriate, validate through testing that\plain\cf1\f51\fs20\ql controls are functioning as documented, and implement a continuous reporting and improvement process for internal control over\plain\cf1\f51\fs20\ql financial reporting. Despite our efforts, there is a risk that we will not be able to conclude, within the prescribed timeframe or at\plain\cf1\f51\fs20\ql all, that our internal control over financial reporting is effective as required by SOX Section\~404. If we identify one or more\plain\cf1\f51\fs20\ql material weaknesses, it could result in an adverse reaction in the financial markets due to a loss of confidence in the reliability of\plain\cf1\f51\fs20\ql our financial statements.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql The Market Price Of Our Common Shares Has Been Volatile and Fluctuate Substantially, Which Could Result In\plain\cf1\f51\fs20\i\ql Substantial Losses For Shareholders.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Our share price has been and in the future, may be subject to substantial volatility. In addition, the stock market in general,\plain\cf1\f51\fs20\ql and Nasdaq listed and biopharmaceutical companies in particular, have experienced extreme price and volume fluctuations that\plain\cf1\f51\fs20\ql have often been unrelated or disproportionate to the operating performance of these companies. For example, our shares traded\plain\cf1\f51\fs20\ql within a range of a high price of $25.00 and a low price of $11.63\~per share for the period beginning on October 19, 2016, our\plain\cf1\f51\fs20\ql first day of trading on the Nasdaq Global Market, through December 29, 2017. As a result of this volatility, our shareholders\plain\cf1\f51\fs20\ql could incur substantial losses. In addition, the market price for our common shares may be influenced by many factors, including:
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\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql commencement or termination of collaborations for our product development and research programs;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
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{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
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{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
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{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql general economic, industry and market conditions; and\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\cf1\f51\fs12\ql \~
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{\trowd\cellx432\cellx1116\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\cf1\f51\fs20\ql the other factors described in this \u8220?Risk Factors\u8221? section.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh248\row}}}\pard\plain\sb264\cf1\f51\fs20\qc 73\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql These and other market and industry factors may cause the market price and demand for our common shares to fluctuate\plain\cf1\f51\fs20\ql substantially, regardless of our actual operating performance, which may limit or prevent investors from readily selling their\plain\cf1\f51\fs20\ql common shares and may otherwise negatively affect the liquidity of our common shares. In the past, when the market price of a\plain\cf1\f51\fs20\ql stock has been volatile, holders of that stock have instituted securities class action litigation against the company that issued the\plain\cf1\f51\fs20\ql stock. If any of our shareholders brought a lawsuit against us, we could incur substantial costs defending the lawsuit. Such a\plain\cf1\f51\fs20\ql lawsuit could also divert the time and attention of our management.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql If Securities Analysts Do Not Publish Research Or Reports About Our Business Or If They Publish Negative Evaluations\plain\cf1\f51\fs20\i\ql Of Our Common Shares, The Price Of Our Common Shares Could Decline.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql The trading market for our common shares will rely in part on the research and reports that industry or financial analysts\plain\cf1\f51\fs20\ql publish about us or our business. If one or more of the analysts covering our business downgrade their evaluations of our\plain\cf1\f51\fs20\ql common shares, the price of our common shares could decline. If one or more of these analysts cease to cover our common\plain\cf1\f51\fs20\ql shares, we could lose visibility in the market for our common shares, which in turn could cause our common share price to\plain\cf1\f51\fs20\ql decline.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql A Significant Portion Of Our Total Outstanding Common Shares May Be Sold Into The Market In The Near Future, Which\plain\cf1\f51\fs20\i\ql Could Cause The Market Price Of Our Common Shares To Decline Significantly, Even If Our Business Is Doing Well.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Sales of a substantial number of our common shares in the public market could occur at any time. These sales, or the\plain\cf1\f51\fs20\ql perception in the market that the holders of a large number of common shares intend to sell shares, could reduce the market price\plain\cf1\f51\fs20\ql of our common stock.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql All lock-up agreements entered into in connection with our initial public offering are expected to expire on April 17, 2017.\plain\cf1\f51\fs20\ql Following the lockup expiration, outstanding common shares may be freely sold in the public market at any time to the extent\plain\cf1\f51\fs20\ql permitted by Rules 144 and 701 under the Securities Act of 1933, as amended (the \u8220?Securities Act\u8221?), or to the\plain\cf1\f51\fs20\ql extent that such shares have already been registered under the Securities Act and are held by non-affiliates of ours.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Moreover, holders of a substantial number of our common shares have rights, subject to conditions, to require us to file\plain\cf1\f51\fs20\ql registration statements covering their shares or to include their shares in registration statements that we may file for ourselves or\plain\cf1\f51\fs20\ql other stockholders. We also have registered substantially all common shares that we may issue under our equity compensation\plain\cf1\f51\fs20\ql plans or that are issuable upon exercise of outstanding options. These common shares can be freely sold in the public market\plain\cf1\f51\fs20\ql upon issuance and once vested, subject to volume limitations applicable to affiliates. If any of these additional common shares\plain\cf1\f51\fs20\ql are sold, or if it is perceived that they will be sold, in the public market, the market price of our common shares could decline.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Our Executive Officers, Directors, And Principal Stockholders, If They Choose To Act Together, Have The Ability To\plain\cf1\f51\fs20\i\ql Control All Matters Submitted To Stockholders For Approval.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql As of February 28, 2018, common shares beneficially owned by our executive officers, directors and principal shareholders,\plain\cf1\f51\fs20\ql including Vertex, Bayer Healthcare and other shareholders and their affiliates who owned more than 5% of our outstanding\plain\cf1\f51\fs20\ql common shares totaled 26,538,395. As a result, these shareholders, if they were to act together, would be able to influence our\plain\cf1\f51\fs20\ql management and affairs and all matters requiring shareholder approval, including the election of directors and approval of\plain\cf1\f51\fs20\ql significant corporate transactions. This concentration of ownership may have the effect of delaying or preventing a change in\plain\cf1\f51\fs20\ql control of our company and might affect the market price of our common shares.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql We Have Broad Discretion In The Use Of Our Cash Reserves And May Not Use Such Cash Reserves Effectively\plain\cf1\f51\fs20\b\i\ql .\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Our management has broad discretion to use our cash reserves and could use our cash reserves in ways that do not improve\plain\cf1\f51\fs20\ql our results of operations or enhance the value of our common shares.\~The failure by our management to apply these funds\plain\cf1\f51\fs20\ql effectively could result in financial losses that could have a material adverse effect on our business, cause the price of our\plain\cf1\f51\fs20\ql common shares to decline, and delay the development of our product candidates. Pending their use, we may invest our cash\plain\cf1\f51\fs20\ql reserves in a manner that does not produce income or that loses value.\par\pard\plain\sb264\cf1\f51\fs20\qc 74\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql We Are An \u8220?Emerging Growth Company,\u8221? And The Reduced Disclosure Requirements Applicable To\plain\cf1\f51\fs20\i\ql Emerging Growth Companies May Make Our Common Shares Less Attractive To Investors.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We are an \u8220?emerging growth company,\u8221? as defined in the Jumpstart Our Business Startups Act of 2012, or\plain\cf1\f51\fs20\ql the JOBS Act. We will remain an emerging growth company until the earlier of (i)\~the last day of the fiscal year in which we\plain\cf1\f51\fs20\ql have total annual gross revenue of $1.07\~billion or more; (ii)\~December 31, 2021, being the last day of the fiscal year following\plain\cf1\f51\fs20\ql the fifth anniversary of the date of the completion of the IPO; (iii)\~the date on which we have issued more than $1\~billion in\plain\cf1\f51\fs20\ql nonconvertible debt during the previous three years; or (iv)\~the date on which we are deemed to be a large accelerated filer under\plain\cf1\f51\fs20\ql the rules of the Securities and Exchange Commission, which means the market value of our common shares that is held by\plain\cf1\f51\fs20\ql non-affiliates exceeds $700\~million as of the prior June\~30th. For so long as we remain an emerging growth company, we are\plain\cf1\f51\fs20\ql permitted and intend to rely on exemptions from certain disclosure requirements that are applicable to other public companies\plain\cf1\f51\fs20\ql that are not emerging growth companies. These exemptions include:
\par\pard\plain
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\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql not being required to comply with any requirement that may be adopted by the Public Company Accounting\plain\intbl\cf1\f51\fs20\ql Oversight Board regarding mandatory audit firm rotation or a supplement to the auditor\u8217?s report providing\plain\intbl\cf1\f51\fs20\ql additional information about the audit and the financial statements;\cell{
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\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql being permitted to present only two years of audited financial statements in addition to any required unaudited\plain\intbl\cf1\f51\fs20\ql interim financial statements with correspondingly reduced \u8220?Management\u8217?s Discussion and Analysis of\plain\intbl\cf1\f51\fs20\ql Financial Condition and Results of Operations\u8221? disclosure in this Annual Report on Form 10-K;\cell{
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\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the \u8220?say on pay\u8221? provisions (requiring a non-binding shareholder vote to approve compensation of\plain\intbl\cf1\f51\fs20\ql certain executive officers) the \u8220?say on golden parachute\u8221? provisions (requiring a non-binding\plain\intbl\cf1\f51\fs20\ql shareholder vote to approve golden parachute arrangements for certain executive officers in connection with mergers\plain\intbl\cf1\f51\fs20\ql and certain other business combinations) of the Dodd-Frank Wall Street Reform and Protection Act, or Dodd-Frank\plain\intbl\cf1\f51\fs20\ql Act, and some of the disclosure requirements of the Dodd-Frank Act relating to compensation of our chief\plain\intbl\cf1\f51\fs20\ql executive officer.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh1620\row}}}\pard\plain\sb264\fi528\cf1\f51\fs20\ql We may choose to take advantage of some, but not all, of the available exemptions. We cannot predict whether investors\plain\cf1\f51\fs20\ql will find our common shares less attractive if we rely on these exemptions. If some investors find our common shares less\plain\cf1\f51\fs20\ql attractive as a result, there may be a less active trading market for our common shares and our common share price may be more\plain\cf1\f51\fs20\ql volatile.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql In addition, the JOBS Act provides that an emerging growth company can take advantage of an extended transition period\plain\cf1\f51\fs20\ql for complying with new or revised accounting standards. This allows an emerging growth company to delay the adoption of\plain\cf1\f51\fs20\ql certain accounting standards until those standards would otherwise apply to private companies. We have irrevocably elected not\plain\cf1\f51\fs20\ql to avail ourselves of this exemption from new or revised accounting standards and, therefore, we will be subject to the same new\plain\cf1\f51\fs20\ql or revised accounting standards as other public companies that are not emerging growth companies.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql We Do Not Expect To Pay Dividends In The Foreseeable Future.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We have not paid any dividends since our incorporation. Even if future operations lead to significant levels of distributable\plain\cf1\f51\fs20\ql profits, we currently intend that any earnings will be reinvested in our business and that no dividends will be paid prior to the\plain\cf1\f51\fs20\ql time we have an established revenue stream to support continuing dividends. The proposal to pay future dividends to shareholders\plain\cf1\f51\fs20\ql will in addition effectively be at the discretion of our board of directors and shareholders after taking into account various factors\plain\cf1\f51\fs20\ql including our business prospects, cash requirements, financial performance and new product development. In addition, payment of\plain\cf1\f51\fs20\ql future dividends is subject to certain limitations pursuant to Swiss law or by our articles of association. Accordingly, investors\plain\cf1\f51\fs20\ql cannot rely on dividend income from our common shares and any returns on an investment in our common shares will likely\plain\cf1\f51\fs20\ql depend entirely upon any future appreciation in the price of our common shares. Dividends, if any, paid on our common shares\plain\cf1\f51\fs20\ql are subject to Swiss federal withholding tax, except if paid out of reserves from capital contributions\plain\cf1\f51\fs20\ql (\u8220?\plain\cf1\f51\fs20\i\ql Kapitaleinlagen\plain\cf1\f51\fs20\ql \u8221?).\par\pard\plain\sb264\cf1\f51\fs20\qc 75\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql We Are A Swiss Corporation. The Rights Of Our Shareholders May Be Different From The Rights Of Shareholders In\plain\cf1\f51\fs20\i\ql Companies Governed By The Laws Of U.S. Jurisdictions.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We are a Swiss corporation. Our corporate affairs are governed by our articles of association and by Swiss law. The rights\plain\cf1\f51\fs20\ql of our shareholders and the responsibilities of members of our board of directors may be different from the rights and obligations\plain\cf1\f51\fs20\ql of shareholders and directors of companies governed by the laws of U.S. jurisdictions. In the performance of its duties, our board\plain\cf1\f51\fs20\ql of directors is required by Swiss law to consider the interests of our Company, our shareholders and our employees with due\plain\cf1\f51\fs20\ql observation of the principles of reasonableness and fairness. It is possible that the board of directors will consider interests that\plain\cf1\f51\fs20\ql are different from, or in addition to, your interests as a shareholder. Swiss corporate law limits the ability of our shareholders to\plain\cf1\f51\fs20\ql challenge resolutions made or other actions taken by our board of directors in court. Our shareholders generally are not permitted\plain\cf1\f51\fs20\ql to file a suit to reverse a decision or an action taken by our board of directors but are instead only permitted to seek damages for\plain\cf1\f51\fs20\ql breaches of the duty of care and loyalty. As a matter of Swiss law, shareholder claims against a member of our board of\plain\cf1\f51\fs20\ql directors for breach of the duty of care and loyalty would have to be brought in Zug, Switzerland, or where the relevant member\plain\cf1\f51\fs20\ql of our board of directors is domiciled. In addition, under Swiss law, any claims by our shareholders against us must be brought\plain\cf1\f51\fs20\ql exclusively in Zug, Switzerland.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Our Common Shares Are Issued Under The Laws Of Switzerland, Which May Not Protect Investors In A Similar Fashion\plain\cf1\f51\fs20\i\ql Afforded By Incorporation In A U.S. State.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We are organized under the laws of Switzerland. However, there can be no assurance that Swiss law will not change in the\plain\cf1\f51\fs20\ql future or that it will serve to protect investors in a similar fashion afforded under corporate law principles in the U.S., which\plain\cf1\f51\fs20\ql could adversely affect the rights of investors.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Our Status As A Swiss Corporation Means That Our Shareholders Enjoy Certain Rights That May Limit Our Flexibility To\plain\cf1\f51\fs20\i\ql Raise Capital, Issue Dividends And Otherwise Manage Ongoing Capital Needs And May Cause Us To Be Unable To Make\plain\cf1\f51\fs20\i\ql Distributions Without Subjecting Our Shareholders To Swiss Withholding Tax.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Swiss law allows our shareholders to authorize share capital that can be issued by the board of directors without additional\plain\cf1\f51\fs20\ql shareholder approval. This authorization is limited to 50% of the existing registered share capital and must be renewed by the\plain\cf1\f51\fs20\ql shareholders every two years. Additionally, subject to specified exceptions, Swiss law grants preemptive rights to existing\plain\cf1\f51\fs20\ql shareholders to subscribe to any new issuance of shares. Swiss law also does not provide as much flexibility in the various terms\plain\cf1\f51\fs20\ql that can attach to different classes of shares as the laws of some other jurisdictions. Swiss law also reserves for approval by\plain\cf1\f51\fs20\ql shareholders certain corporate actions over which a board of directors would have authority in some other jurisdictions. For\plain\cf1\f51\fs20\ql example, the payment of dividends and the cancellation of treasury shares must be approved by shareholders. These Swiss law\plain\cf1\f51\fs20\ql requirements relating to our capital management may limit our flexibility, and situations may arise where greater flexibility would\plain\cf1\f51\fs20\ql have provided substantial benefits to our shareholders.\par\pard\plain\cf1\f51\fs24\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql Under Swiss law, a Swiss corporation may pay dividends only if the corporation has sufficient distributable profits from\plain\cf1\f51\fs20\ql previous fiscal years, or if the corporation has distributable reserves, each as evidenced by its audited statutory balance sheet, and\plain\cf1\f51\fs20\ql after allocations to reserves required by Swiss law and our articles of association have been deducted. Freely distributable\plain\cf1\f51\fs20\ql reserves are generally booked either as \u8220?free reserves\u8221? or as \u8220?capital contributions\u8221? (\plain\cf1\f51\fs20\i\ql Kapitaleinlagen\plain\cf1\f51\fs20\ql ,\plain\cf1\f51\fs20\ql contributions received from shareholders) in the \u8220?reserve from capital contributions.\u8221? Distributions may be made out\plain\cf1\f51\fs20\ql of registered share capital\u8212?the aggregate par value of a company\u8217?s registered shares\u8212?only by way of a capital\plain\cf1\f51\fs20\ql reduction. We will not be able to pay dividends or make other distributions to shareholders on a Swiss withholding tax-free basis\plain\cf1\f51\fs20\ql in excess of our aggregate qualifying contributions and registered share capital unless we increase our share capital or our\plain\cf1\f51\fs20\ql reserves from capital contributions. We would also be able to pay dividends out of distributable profits or freely distributable\plain\cf1\f51\fs20\ql reserves, but such dividends would be subject to Swiss withholding taxes. There can be no assurance that we will have sufficient\plain\cf1\f51\fs20\ql distributable profits, free reserves, reserves from capital contributions or registered share capital to pay a dividend or effect a\plain\cf1\f51\fs20\ql capital reduction, that our shareholders will approve dividends or capital reductions proposed by us or that we will be able to\plain\cf1\f51\fs20\ql meet the other legal requirements for dividend payments or distributions as a result of capital reductions.\par\pard\plain\sb264\cf1\f51\fs20\qc 76\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Generally, Swiss withholding tax of 35% is due on dividends and similar distributions to our shareholders, regardless of the\plain\cf1\f51\fs20\ql place of residency of the shareholder, unless the distribution is made to shareholders out of (i)\~a reduction of registered share\plain\cf1\f51\fs20\ql capital or (ii)\~assuming certain conditions are met, qualifying capital contribution reserves, as further described under\plain\cf1\f51\fs20\ql \u8220?Taxation\u8212?Swiss Tax Considerations\u8212?Swiss Federal Withholding Tax\u8221?. A U.S. holder that qualifies for\plain\cf1\f51\fs20\ql benefits under the Convention between the United States of America and Switzerland for the Avoidance of Double Taxation with\plain\cf1\f51\fs20\ql Respect to Taxes on Income, or the U.S.-Swiss Treaty, may apply for a refund of the tax withheld in excess of the 15% treaty\plain\cf1\f51\fs20\ql rate (or in excess of the 5% reduced treaty rate for qualifying corporate shareholders with at least 10% participation in our voting\plain\cf1\f51\fs20\ql shares, or for a full refund in the case of qualified pension funds). There can be no assurance that we will have sufficient\plain\cf1\f51\fs20\ql qualifying capital contribution reserves to pay dividends free from Swiss withholding tax, or that Swiss withholding rules will not\plain\cf1\f51\fs20\ql be changed in the future. In addition, we cannot provide assurance that the current Swiss law with respect to distributions out of\plain\cf1\f51\fs20\ql qualifying capital contribution reserves will not be changed or that a change in Swiss law will not adversely affect us or our\plain\cf1\f51\fs20\ql shareholders, in particular as a result of distributions out of qualifying capital contribution reserves becoming subject to additional\plain\cf1\f51\fs20\ql corporate law or other restrictions. There are currently ongoing discussions in the Swiss Parliament that may limit the distribution\plain\cf1\f51\fs20\ql of qualifying capital contributions. In addition, over the long term, the amount of registered share capital available to us for\plain\cf1\f51\fs20\ql registered share capital reductions or qualifying capital contributions available to us to pay out as distributions is limited. If we\plain\cf1\f51\fs20\ql are unable to make a distribution through a reduction in par value or out of qualifying capital contributions, we may not be able\plain\cf1\f51\fs20\ql to make distributions without subjecting our shareholders to Swiss withholding taxes.\par\pard\plain\cf1\f51\fs24\ql \~\par\pard\plain\fi528\cf1\f51\fs20\ql Under present Swiss tax laws, repurchases of shares for the purposes of cancellation are treated as a partial liquidation\plain\cf1\f51\fs20\ql subject to 35% Swiss withholding tax on the difference between the repurchase price and the par value except, since January\~1,\plain\cf1\f51\fs20\ql 2011, to the extent attributable to qualifying capital contributions (\plain\cf1\f51\fs20\i\ql Kapitaleinlagen\plain\cf1\f51\fs20\ql ) if any, the Swiss withholding becomes due.\plain\cf1\f51\fs20\ql No partial liquidation treatment applies and no withholding tax is triggered if the shares are not repurchased for cancellation but\plain\cf1\f51\fs20\ql held by us as treasury shares. However, should we not resell such treasury shares within six years, the withholding tax becomes\plain\cf1\f51\fs20\ql due at the end of the six-year period.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Certain U.S. Shareholders May Be Subject To Adverse U.S. Federal Income Tax Consequences If We Are A Controlled\plain\cf1\f51\fs20\i\ql Foreign Corporation.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Each \u8220?Ten Percent Shareholder\u8221? (as defined below) in a non-U.S. corporation that is classified as a\plain\cf1\f51\fs20\ql \u8220?controlled foreign corporation,\u8221? or a CFC, for United States federal income tax purposes generally is required to\plain\cf1\f51\fs20\ql include in income for U.S. federal tax purposes such Ten Percent Shareholder\u8217?s pro rata share of the CFC\u8217?s\plain\cf1\f51\fs20\ql \u8220?Subpart F income\u8221? and investment of earnings in U.S. property, even if the CFC has made no distributions to its\plain\cf1\f51\fs20\ql shareholders. Subpart F income generally includes dividends, interest, rents and royalties, gains from the sale of securities and\plain\cf1\f51\fs20\ql income from certain transactions with related parties. In addition, a Ten Percent Shareholder that realizes gain from the sale or\plain\cf1\f51\fs20\ql exchange of shares in a CFC may be required to classify a portion of such gain as dividend income rather than capital gain. A\plain\cf1\f51\fs20\ql non-U.S. corporation generally will be classified as a CFC for United States federal income tax purposes if Ten Percent\plain\cf1\f51\fs20\ql Shareholders own, directly or indirectly, more than 50% of either the total combined voting power of all classes of stock of such\plain\cf1\f51\fs20\ql corporation entitled to vote or of the total value of the stock of such corporation. A \u8220?Ten Percent Shareholder\u8221? is a\plain\cf1\f51\fs20\ql United States person (as defined by the U.S. Internal Revenue Code of 1986, as amended (the \u8220?Code\u8221?)) who owns\plain\cf1\f51\fs20\ql or is considered to own 10% or more of the total combined voting power of all classes of stock entitled to vote of such\plain\cf1\f51\fs20\ql corporation. The determination of CFC status is complex and includes attribution rules, the application of which is not entirely\plain\cf1\f51\fs20\ql certain.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql During our 2017 taxable year we believe that we had certain shareholders that were Ten Percent Shareholders for United\plain\cf1\f51\fs20\ql States federal income tax purposes. However, our CFC status for the taxable year ended December 31, 2017 and our current\plain\cf1\f51\fs20\ql taxable year is unknown and we may be a CFC for the taxable year ended December 31, 2017, our current taxable year or a\plain\cf1\f51\fs20\ql following year. In addition, recent changes to the attribution rules relation to the determination of CFC status may make it\plain\cf1\f51\fs20\ql difficult to determine our CFC status for any taxable year. U.S. holders should consult their own tax advisors with respect to the\plain\cf1\f51\fs20\ql potential adverse U.S. tax consequences of becoming a Ten Percent Shareholder in a CFC. If we are classified as both a CFC\plain\cf1\f51\fs20\ql and a PFIC, we generally will not be treated as a PFIC with respect to those U.S. holders that meet the definition of a Ten\plain\cf1\f51\fs20\ql Percent Shareholder during the period in which we are a CFC.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Certain U.S. Shareholders May Be Subject to Adverse Tax Consequences If We Are A Passive Foreign Investment\plain\cf1\f51\fs20\i\ql Company.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Generally, if, for any taxable year, at least 75% of our gross income is passive income, or at least 50% of the value of our\plain\cf1\f51\fs20\ql assets is attributable to assets that produce passive income or are held for the production of passive income, including cash, we\plain\cf1\f51\fs20\ql would be characterized as a PFIC, for U.S. federal income tax purposes. For purposes of these tests, passive income includes\plain\cf1\f51\fs20\ql dividends, interest, and gains from the sale or exchange of investment property and rents and royalties other than rents and\plain\cf1\f51\fs20\ql royalties which are received from unrelated parties in connection with the active conduct of a trade or business. If we are\plain\cf1\f51\fs20\ql characterized as a PFIC, U.S. holders of our common shares may suffer adverse tax consequences, including having gains\plain\cf1\f51\fs20\ql realized on the sale of the common shares treated as ordinary income, rather than capital gain, the loss of the preferential rate\plain\cf1\f51\fs20\ql applicable to dividends received on the common shares by individuals who are U.S. holders, and having interest charges apply to\plain\cf1\f51\fs20\ql distributions by us and the proceeds of sales of the common shares.\par\pard\plain\sb264\cf1\f51\fs20\qc 77\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Our status as a PFIC will depend on the composition of our income and the composition and value of our assets which\plain\cf1\f51\fs20\ql may be determined in part by reference to the quarterly market value of our common shares, which may be volatile. Our status\plain\cf1\f51\fs20\ql may also depend, in part, on how, and how quickly, we utilize the cash proceeds from the IPO in our business. Our status as a\plain\cf1\f51\fs20\ql PFIC is a fact-intensive determination made on an annual basis and we cannot provide any assurances regarding our PFIC status\plain\cf1\f51\fs20\ql for any past, current or future taxable years.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Because it is possible we were a PFIC for the 2016 taxable year, we provided the information that is necessary for you to\plain\cf1\f51\fs20\ql make a QEF election with respect to us for the 2016 taxable year on our website (www.crisprtx.com). In addition, although we\plain\cf1\f51\fs20\ql have not yet determined whether\~\~we are a PFIC for the 2017 taxable year, it is possible that we may be a PFIC for the 2017\plain\cf1\f51\fs20\ql taxable year as well. We will endeavor to provide you, for each taxable year that we determine we are a PFIC, a PFIC Annual\plain\cf1\f51\fs20\ql Information Statement containing information necessary for you to make a QEF election with respect to us.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql If we are determined to be a PFIC, a U.S. holder will generally be treated as owning a proportionate amount (by value) of\plain\cf1\f51\fs20\ql shares owned by us in any of our direct or indirect subsidiaries that are also PFICs, each a lower-tier PFIC, and will be subject\plain\cf1\f51\fs20\ql to similar adverse rules with respect to distributions from, or dispositions of, such lower-tier PFICs, in each case as if such U.S.\plain\cf1\f51\fs20\ql holder held such shares directly (even if such U.S. holder does not receive the proceeds of such distributions or dispositions\plain\cf1\f51\fs20\ql directly). We have not determined whether any of our subsidiaries (including TRACR Hematology Ltd. and CRISPR\plain\cf1\f51\fs20\ql Therapeutics Ltd.) are or may be lower-tier PFICs for any prior taxable year, the current taxable year or future taxable years, and\plain\cf1\f51\fs20\ql we do not intend to do so. We also do not intend to make available the information necessary for U.S. holders to make a QEF\plain\cf1\f51\fs20\ql election with respect to any lower-tier PFICs and therefore you should expect that you will not be able to make a QEF election\plain\cf1\f51\fs20\ql with respect to them.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql You are urged to consult your own tax advisors regarding our PFIC status and the tax considerations relevant to an\plain\cf1\f51\fs20\ql investment in a PFIC, including the availability, and advisability, of, and procedure for making, a QEF election with respect to\plain\cf1\f51\fs20\ql us, and the application of the PFIC rules to any of our subsidiaries.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql Comprehensive Tax Reform Legislation Could Adversely Affect Our Business And Financial Condition.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql On December 22, 2017, the \u8220?Tax Cuts and Jobs Act\u8221? (TCJA) was enacted.\~\~The TCJA significantly reforms\plain\cf1\f51\fs20\ql the Internal Revenue Code of 1986, as amended (the \u8220?Code\u8221?). The TCJA, among other things, includes changes to\plain\cf1\f51\fs20\ql U.S. federal tax rates, imposes significant additional limitations on the deductibility of interest and net operating loss\plain\cf1\f51\fs20\ql carryforwards, allows for the expensing of capital expenditures, and puts into effect the migration from a\plain\cf1\f51\fs20\ql \u8220?worldwide\u8221? system of taxation to a territorial system.\~We continue to examine the impact this tax reform\plain\cf1\f51\fs20\ql legislation may have on our business. The impact of this tax reform is uncertain and could be adverse.\par\pard\plain\sb396\fi528\cf1\f51\fs20\i\ql U.S. Shareholders May Not Be Able To Obtain Judgments Or Enforce Civil Liabilities Against Us Or Our Executive\plain\cf1\f51\fs20\i\ql Officers Or Members Of Our Board Of Directors.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql We are a Swiss corporation organized under the laws of Switzerland and our registered office and domicile is located in\plain\cf1\f51\fs20\ql Basel, Switzerland. Moreover, certain of our directors and executive officers and a number of directors of each of our subsidiaries\plain\cf1\f51\fs20\ql are not residents of the United States, and all or a substantial portion of the assets of such persons are located outside the United\plain\cf1\f51\fs20\ql States. As a result, it may not be possible for investors to effect service of process within the United States such persons or to\plain\cf1\f51\fs20\ql enforce against them judgments obtained in U.S. courts, including judgments in actions predicated upon the civil liability\plain\cf1\f51\fs20\ql provisions of the federal securities laws of the United States. We have been advised by our Swiss counsel that there is doubt as\plain\cf1\f51\fs20\ql to the enforceability in Switzerland of original actions, or in actions for enforcement of judgments of U.S. courts, of civil\plain\cf1\f51\fs20\ql liabilities to the extent solely predicated upon the federal and state securities laws of the United States. Original actions against\plain\cf1\f51\fs20\ql persons in Switzerland based solely upon the U.S. federal or state securities laws are governed, among other things, by the\plain\cf1\f51\fs20\ql principles set forth in the Swiss Federal Act on Private International Law. This statute provides that the application of provisions\plain\cf1\f51\fs20\ql of non-Swiss law by the courts in Switzerland shall be precluded if the result is incompatible with Swiss public policy. Also,\plain\cf1\f51\fs20\ql mandatory provisions of Swiss law may be applicable regardless of any other law that would otherwise apply.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql Switzerland and the United States do not have a treaty providing for reciprocal recognition and enforcement of judgments\plain\cf1\f51\fs20\ql in civil and commercial matters. The recognition and enforcement of a judgment of the courts of the United States in Switzerland\plain\cf1\f51\fs20\ql is governed by the principles set forth in the Swiss Federal Act on Private International Law. This statute provides in principle\plain\cf1\f51\fs20\ql that a judgment rendered by a non-Swiss court may be enforced in Switzerland only if:
\par\pard\plain
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\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the non-Swiss court had jurisdiction pursuant to the Swiss Federal Act on Private International Law;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql the judgment of such non-Swiss court has become final and non-appealable;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}\pard\plain\sb264\cf1\f51\fs20\qc 78\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~
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\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\pard\plain\intbl\sb132\cf1\f51\fs20\ql the court procedures and the service of documents leading to the judgment were in accordance with the due process\plain\intbl\cf1\f51\fs20\ql of law; and\cell{
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\pard\plain\intbl\sb132\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\ql no proceeding involving the same position and the same subject matter was first brought in Switzerland, or\plain\intbl\cf1\f51\fs20\ql adjudicated in Switzerland, or was earlier adjudicated in a third state and this decision is recognizable in\plain\intbl\cf1\f51\fs20\ql Switzerland.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh878\row}}}{\*\bkmkstart item_1_3_4}{\*\bkmkend item_1_3_4}{\*\bkmkstart item_1b_unresolved_staff_comment}{\*\bkmkend item_1b_unresolved_staff_comment}\pard\plain\sb396\cf1\f51\fs20\b\ql Item 1B. Unresolved Staff Comments.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql None.{\*\bkmkstart item_1_3_5}{\*\bkmkend item_1_3_5}{\*\bkmkstart item_2_properties_12116663}{\*\bkmkend item_2_properties_12116663}\par\pard\plain\sb396\cf1\f51\fs20\b\ql Item 2. Properties.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Our principal executive offices are located in Zug, Switzerland pursuant to a real estate lease agreement with a term that\plain\cf1\f51\fs20\ql renews every six months. We also have facilities in Cambridge, Massachusetts, where we occupy approximately 65,376 square\plain\cf1\f51\fs20\ql feet of laboratory and office space under a sublease that expires in December 2026. We also lease approximately 19,817 square\plain\cf1\f51\fs20\ql feet of additional office and laboratory space in Cambridge, Massachusetts pursuant to a lease that expires in February 2022. In\plain\cf1\f51\fs20\ql London, England, we occupy and maintain office space pursuant to a real estate lease agreement with a term that renews every\plain\cf1\f51\fs20\ql six months. We believe that our facilities are adequate for our current needs and that suitable additional or substitute space would\plain\cf1\f51\fs20\ql be available if needed.\par\pard\plain\cf1\f51\fs18\ql \~{\*\bkmkstart item_1_3_6}{\*\bkmkend item_1_3_6}{\*\bkmkstart item_3_legal_proceedings_1211666}{\*\bkmkend item_3_legal_proceedings_1211666}\par\pard\plain\sb198\cf1\f51\fs20\b\ql Item 3. Legal Proceedings.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql From time to time, we may become involved in litigation or other legal proceedings relating to claims arising from the\plain\cf1\f51\fs20\ql ordinary course of business. There are currently no claims or actions pending against us that, in the opinion of our management,\plain\cf1\f51\fs20\ql are likely to have a material adverse effect on our business. In January 2016, the United States Patent and Trademark Office, or\plain\cf1\f51\fs20\ql USPTO, declared an interference between one of the pending U.S. patent applications we have in-licensed from Dr. Charpentier\plain\cf1\f51\fs20\ql and twelve issued U.S. patents and one U.S. patent application owned jointly by The Broad Institute, Massachusetts Institute of\plain\cf1\f51\fs20\ql Technology, President and Fellows of Harvard College, or Broad. The interference was redeclared in March 2016 to add a U.S.\plain\cf1\f51\fs20\ql patent application owned by Broad. An interference is a proceeding conducted at the USPTO by the Patent Trial and Appeal\plain\cf1\f51\fs20\ql Board, or PTAB, to determine which party was first to invent subject matter by at least two parties.\~There are currently two\plain\cf1\f51\fs20\ql parties to this interference.\~Our in-licensed patent application is co-owned among Dr. Charpentier, the Regents of the University\plain\cf1\f51\fs20\ql of California, and the University of Vienna, whom the USPTO designated collectively as \u8220?Senior Party\u8221?; Broad was\plain\cf1\f51\fs20\ql designated as \u8220?Junior Party.\u8221?\~Following motions by the parties and other procedural matters, the PTAB concluded in\plain\cf1\f51\fs20\ql February 2017 that the declared interference should be dismissed because the claim sets of the two parties were not directed to\plain\cf1\f51\fs20\ql the same patentable invention in accordance with the PTAB\u8217?s two-way test for patent interferences. In particular, the\plain\cf1\f51\fs20\ql Junior Party\u8217?s claims in the interference were all limited to uses in eukaryotic cells, while the Senior Party\u8217?s claims\plain\cf1\f51\fs20\ql in the interference were not limited to uses in eukaryotic cells but included uses in all settings. Senior Party appealed the decision\plain\cf1\f51\fs20\ql to the U.S. Court of Appeals for the Federal Circuit. In parallel, either party can also pursue existing or new patent applications\plain\cf1\f51\fs20\ql in the U.S. and elsewhere. Going forward, either party as well as other parties could seek a new interference related to the uses\plain\cf1\f51\fs20\ql of the technology in eukaryotic cells or other aspects of the technology, and any existing or new patents could be the subject of\plain\cf1\f51\fs20\ql other challenges to their validity of enforceability. In the context of a second interference or in other proceedings, a determination\plain\cf1\f51\fs20\ql could be reached regarding that the Senior Party was not the first to invent, or it could be concluded that the contested subject\plain\cf1\f51\fs20\ql matter is not patentable to the Senior Party and is patentable to the Junior Party, which in this case could preclude our U.S.\plain\cf1\f51\fs20\ql patent applications from issuing as patents, in which case the proceedings would result in our losing the right to protect core\plain\cf1\f51\fs20\ql innovations and our freedom to practice our core gene editing technology. If there is a second interference, either party could\plain\cf1\f51\fs20\ql again appeal an adverse decision to the U.S. Court of Appeals for the Federal Circuit. In any case, it may be years before there is\plain\cf1\f51\fs20\ql a final determination on priority.\~In addition, both the Broad Toolgen Inc. and Sigma have filed international counterparts of their\plain\cf1\f51\fs20\ql U.S. applications, some of which were granted in Europe and/or other jurisdictions, and Vilnius University and other third parties\plain\cf1\f51\fs20\ql also have international counterparts of U.S. patent applications that could proceed to grant. We and third parties have initiated\plain\cf1\f51\fs20\ql opposition proceedings against some of these grants, and we may in the future oppose other grants to these or other applicants.\plain\cf1\f51\fs20\ql Similarly, if we should obtain patent grants in the U.S., Europe and other jurisdictions, these could also be the subject of\plain\cf1\f51\fs20\ql oppositions or other post-grant procedures sought by third parties in order to revoke the grants or narrow the scope of granted\plain\cf1\f51\fs20\ql claims. Going forward, with existing and new challenges being filed against CRISPR/Cas9 cases in the U.S., Europe and\plain\cf1\f51\fs20\ql elsewhere, and considering the number of interested parties, it is reasonable to expect that patents directed to the underlying\plain\cf1\f51\fs20\ql technology will continue to be the subject of ongoing disputes over at least the next several years, and potentially beyond as\plain\cf1\f51\fs20\ql decisions in favor or against particular parties may be the subject of appeals.\par\pard\plain\sb264\fi528\cf1\f51\fs20\ql For further information regarding risks regarding the interference and patent rights held by third parties, please see\plain\cf1\f51\fs20\ql \u8220?Risk Factors\u8212?Risks Related to Our Intellectual Property\u8221? contained in Item 1A of this report.\par\pard\plain\sb264\cf1\f51\fs20\qc 79\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart item_1_3_7}{\*\bkmkend item_1_3_7}{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}{\*\bkmkstart item_4_mine_safety_disclosures_1}{\*\bkmkend item_4_mine_safety_disclosures_1}\par\pard\plain\sb396\cf1\f51\fs20\b\ql Item 4. Mine Safety Disclosures.\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Not applicable.\par\pard\plain\sb264\cf1\f51\fs20\qc 80\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart part_1_2_3}{\*\bkmkend part_1_2_3}{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}{\*\bkmkstart part_ii_12116663}{\*\bkmkend part_ii_12116663}\par\pard\plain\cf1\f51\fs20\b\qc PART II{\*\bkmkstart item_1_3_8}{\*\bkmkend item_1_3_8}{\*\bkmkstart item_5_market_for_registrants_co}{\*\bkmkend item_5_market_for_registrants_co}\par\pard\plain\sb264\cf1\f51\fs20\b\ql Item 5. Market for Registrant\u8217?s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity\plain\cf1\f51\fs20\b\ql Securities.\par\pard\plain\sb132\cf1\f51\fs20\b\ql Market Information\par\pard\plain\sb132\fi528\cf1\f51\fs20\ql Our common stock is traded on The Nasdaq Global Market under the symbol \u8220?CRSP.\u8221? The following table\plain\cf1\f51\fs20\ql sets forth for the periods indicated the high and low sale prices per share of our common stock as reported by Nasdaq Stock\plain\cf1\f51\fs20\ql Market\~LLC:\par\pard\plain\cf1\f51\fs20\b\ql \~
\par\pard\plain
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{\*\bkmkstart _hlk507104357_12116663}{\*\bkmkend _hlk507104357_12116663}\pard\plain\intbl\cf1\f51\fs16\b\ql Year Ended December 31, 2017:\cell\pard\plain\intbl\cf1\f51\fs16\b\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc High\cell\pard\plain\intbl\cf1\f51\fs16\b\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc Low\cell\pard\plain\intbl\cf1\f51\fs16\b\ql \~\cell{
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\pard\plain\intbl\cf1\f51\fs20\ql First quarter\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\cf1\f51\fs20\qr 24.99\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\cf1\f51\fs20\qr 11.63\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
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\pard\plain\intbl\cf1\f51\fs20\ql Second quarter\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 22.22\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 13.50\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
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\pard\plain\intbl\cf1\f51\fs20\ql Third quarter\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 21.32\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 15.55\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
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\pard\plain\intbl\cf1\f51\fs20\ql Fourth quarter\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 25.00\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 16.51\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell{
{\trowd\trqc\clshdng100\clcfpat7\clcbpat7\cellx5798\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx5893\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6081\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7127\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7226\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7321\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7491\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8537\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8640\trrh264\row}}}
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\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f62\fs22\ql \~\cell{
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\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f62\fs22\ql \~\cell{
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\pard\plain\intbl\cf1\f51\fs16\b\ql Year Ended December 31, 2016:\cell\pard\plain\intbl\cf1\f51\fs16\b\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc High\cell\pard\plain\intbl\cf1\f51\fs16\b\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc Low\cell\pard\plain\intbl\cf1\f51\fs16\b\ql \~\cell{
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\pard\plain\intbl\cf1\f51\fs20\ql Fourth quarter\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\cf1\f51\fs20\qr 23.97\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql $\cell\pard\plain\intbl\cf1\f51\fs20\qr 13.75\cell\pard\plain\intbl\cf1\f51\fs2\ql \~\cell{
{\trowd\trqc\clshdng100\clcfpat7\clcbpat7\cellx5798\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx5893\clbrdrt\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx6081\clbrdrt\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7127\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7226\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7321\clbrdrt\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx7491\clbrdrt\brdrs\brdrcf1\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8537\clvertalb\clshdng100\clcfpat7\clcbpat7\cellx8640\trrh281\row}}}\pard\plain\cf1\f51\fs20\b\ql \~\par\pard\plain\sb264\cf1\f51\fs20\qc 81\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb176\cf1\f51\fs20\b\ql Stock Performance Graph\par\pard\plain\cf1\f51\fs12\ql \~{\*\bkmkstart _hlk507433273_12116663}{\*\bkmkend _hlk507433273_12116663}\par\pard\plain\fi528\cf1\f51\fs20\ql The following performance graph and related information shall not be deemed to be \u8220?soliciting material\u8221? or to\plain\cf1\f51\fs20\ql be \u8220?filed\u8221? with the Securities and Exchange Commission, or SEC, for purposes of Section 18 of the Securities\plain\cf1\f51\fs20\ql Exchange Act of 1934, as amended, or the Exchange Act, nor shall such information be incorporated by reference into any future\plain\cf1\f51\fs20\ql filing under the Exchange Act or Securities Act of 1933, as amended, or the Securities Act, except to the extent that we\plain\cf1\f51\fs20\ql specifically incorporate it by reference into such filing.\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb44\fi528\cf1\f51\fs20\ql The graph set forth below compares the cumulative total stockholder return on our shares between October\~19, 2016 (the\plain\cf1\f51\fs20\ql date of our initial public offering) and December\~29, 2017, with the cumulative total return of (a)\~the Nasdaq Biotechnology\plain\cf1\f51\fs20\ql Index and (b)\~the Nasdaq Composite Index, over the same period. This graph assumes the investment of $100 on October\~19,\plain\cf1\f51\fs20\ql 2016 in our common stock, the Nasdaq Biotechnology Index and the Nasdaq Composite Index and assumes the reinvestment of\plain\cf1\f51\fs20\ql dividends, if any. The graph assumes our closing sales price on October\~19, 2016 of $14.09 per share as the initial value of our\plain\cf1\f51\fs20\ql common shares and not the initial offering price to the public of $14.00 per share. The comparisons shown in the graph below\plain\cf1\f51\fs20\ql are based upon historical data. The stock price performance included in this graph is not necessarily indicative of future stock\plain\cf1\f51\fs20\ql price performance.\par\pard\plain\cf1\f51\fs20\qc \~\par\qc{\*\shppict{\pict\pngblip\picw720\pich446\picscalex74\picscaley74\bliptag-8110292286
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